VA Class:CN701

AHFS Class:

• Phenothiazines 28:16.08.24

Associated Monographs

• Chlorpromazine

• Fluphenazine

• Perphenazine

• Prochlorperazine

• Thioridazine

• Trifluoperazine

Phenothiazines are conventional (prototypical, first-generation) antipsychotic agents.

Phenothiazines mainly are used for the management of various psychoneurologic disorders and for the prevention and control of nausea and vomiting. The efficacy of individual phenothiazines varies in different neuropsychiatric and other conditions, and some phenothiazines are not used as antipsychotic agents. Promethazine is used as an antihistamine (see 4:04) and as a sedative (see 28:24.92) and thiethylperazine as an antiemetic. For further information, see the individual monographs on these derivatives.

Psychotic Disorders

Schizophrenia and Other Psychotic Disorders

Phenothiazines are used principally for the symptomatic management of psychotic disorders, especially those characterized by excessive psychomotor activity. The drugs produce substantial improvement in most schizophrenic patients. Phenothiazines are particularly effective in reducing hallucinations and motor and autonomic hyperactivity in patients with schizophrenic disorder; thought disorders, change in affect, and autism are also reduced during phenothiazine therapy. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

General Considerations

Schizophrenia, a major psychotic disorder, is a chronic condition that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors.301,302 Manifestations of the disorder involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment.301,302 The behavioral and psychologic characteristics of schizophrenia are associated with a variety of impairments in social and occupational functioning.301,302 Although marked deterioration associated with impairments in multiple areas of functioning (e.g., learning, self-care, working, interpersonal relationships, living skills) can occur, the disorder is characterized by great interindividual heterogeneity and by intraindividual variability over time.301

The principal manifestations of schizophrenia usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms.301 Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition).301 Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.301 Subtypes of schizophrenia include the paranoid, disorganized, catatonic, undifferentiated, and residual types.301

Management of schizophrenia usually involves a variety of interventions (e.g., psychiatric management, psychosocial interventions, drug therapy, electroconvulsive therapy [ECT]) aimed at reducing or eliminating symptoms, maximizing quality of life and adaptive functioning, and enabling recovery by assisting patients in attaining personal life goals (e.g., in work, housing, relationships).301 The long-term outcome of schizophrenia varies along a continuum between reasonable recovery and complete incapacity.301 Most patients display exacerbations and remissions in the context of experiencing clinical deterioration, although approximately 10-15% of patients are free of further episodes after recovery from a first psychotic episode, and another 10-15% remain chronically severely psychotic.301

Disease Phase Overview

Schizophrenia is a disorder that has been described as developing in phases, which have been characterized as premorbid, prodromal, and psychotic.301 The premorbid phase consists of a period of normal functioning, although certain events (e.g., complications in pregnancy and delivery during the prenatal and perinatal periods, trauma, family stress during childhood and adolescence) may contribute to the development of subsequent illness.301 During the prodromal phase, which lasts an average of 2-5 years, substantial functional impairment, nonspecific symptoms (e.g., sleep disturbance, anxiety, irritability, depressed mood, poor concentration, fatigue), and behavioral deficits (e.g., role functioning deterioration, social withdrawal) develop.301 Positive symptoms (e.g., perceptual abnormalities, ideas of reference, suspiciousness) occur late in the prodromal phase and signal the onset of impending psychosis.301 The onset of the first psychotic episode may be abrupt or insidious, and an average of 1-2 years passes between the first psychotic symptoms and the first adequate treatment in most Western countries.301 The psychotic phase progresses through an acute phase, a stabilization (or recovery) phase, and a stable phase.301

During the acute phase of schizophrenia, patients generally exhibit florid psychotic features such as hallucinations and delusions (positive symptoms), formal thought disorder, and disorganized thinking and usually are unable to care for themselves properly.301 Negative symptoms also often increase in severity.301 Treatment during the acute phase of a psychotic exacerbation is aimed at preventing harm, controlling disturbed behavior, reducing the severity of psychosis and associated symptoms (e.g., agitation, aggression, negative symptoms, affective symptoms), determining and addressing the factors that led to the occurrence of the acute psychotic episode, effecting a rapid return to the best level of functioning, developing an alliance with the patient and family, formulating short- and long-term treatment plans, and connecting the patient with appropriate aftercare in the community.301

During the stabilization (or recovery) phase, which refers to a period of 6-18 months after acute treatment and is characterized by decreasing severity of acute psychotic symptoms, therapy is aimed at sustaining symptom remission or control, minimizing stress, providing support to reduce the likelihood of relapse, enhancing the patient's adaptation to community life, facilitating the continued reduction in symptoms and consolidation of remission, and promoting the process of recovery.301

Once symptoms become relatively stabilized, the disorder enters the stable phase. If symptoms are present during this period, they usually are consistent in magnitude and less severe than during the acute phase.301 Some patients may experience nonpsychotic symptoms such as tension, anxiety, depression, or insomnia during the stable phase.301 Treatment during the stable phase is aimed at sustaining symptom remission or control and maintaining or improving the patient's level of functioning and quality of life, while effectively treating symptoms, preventing relapse, and monitoring for and managing adverse effects.301

Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse.301 Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia.301 Adverse effects also are a critical aspect of antipsychotic therapy in the acute, stabilization, and maintenance phases of a psychotic exacerbation and are often a determining factor in choice of therapy, as well as a principal reason for drug discontinuance.301

Acute Phase

For acute psychotic episodes in patients with schizophrenia, therapy with antipsychotic agents is indicated for almost all patients and should begin as soon as clinically feasible because exacerbations are associated with emotional distress, disruption to the patient's life, and a substantial risk of dangerous behaviors (i.e., to self, others, property).301 Delay of therapy may be reasonable in limited circumstances (e.g., for patients who require more extensive or prolonged diagnostic evaluation, who refuse drug therapy, or who may experience rapid recovery because substance use or acute stress reaction are thought to be potential causes of the symptom exacerbation).301 Before initiation of treatment with an antipsychotic agent, baseline laboratory studies may be indicated.301 In addition, it is important that clinicians assess the patient's ability to participate in drug therapy decisions and, as feasible, discuss the potential risks and benefits of the drug with the patient.301

In patients with an acute psychotic episode who exhibit aggressive behaviors toward self, others, or objects, rapid initiation of emergency treatment is necessary.301 In such situations, existing therapeutic protocols of the emergency department, inpatient unit, or other acute treatment facility should be consulted.301 If a patient refuses drug therapy, emergency administration may be considered if allowed by state law.301 Use of short-acting parenteral formulations of antipsychotic agents (e.g., haloperidol, olanzapine, ziprasidone), with or without a parenteral benzodiazepine (e.g., lorazepam), may be considered in acutely agitated patients.301 Although patients may exhibit a dramatic calming response to an IM dose of a short-acting antipsychotic formulation, this calming effect on agitation should not be misinterpreted as a true antipsychotic effect, which may take several days or weeks of continued therapy to achieve.301 Rapidly dissolving (e.g., olanzapine, risperidone) or oral concentrate (e.g., haloperidol, risperidone) formulations of antipsychotic agents also may be used in acutely agitated patients.301

In less emergent conditions in which the patient refuses drug therapy, the clinician may have limited options, but enlisting family members and psychotherapeutic interactions may be helpful in gaining patient acceptance of treatment.301 The use of advance directives to allow competent patients to state treatment preferences in the event of future decompensation or incapacity to make decisions should be encouraged, when available.301 In some cases, a judicial hearing may be necessary to seek permission to treat a patient who lacks capacity to make such decisions.301

Short-term efficacy of antipsychotic drug therapy generally has been established by reductions in positive (e.g., hallucinations, delusions, bizarre behaviors) and negative (e.g., apathy, affective blunting, alogia, avolition) symptoms associated with schizophrenic psychosis over a 6- to 12-week treatment period; less clear is how such symptomatic improvement relates to improvements in patient functioning.301 Approximately 60% of patients treated with 6 weeks of conventional (first-generation) antipsychotic drug therapy for an acute episode exhibit symptomatic improvement to the point of complete remission or only mildly residual symptomatology, although 40% of patients continue to exhibit moderate to severe psychotic symptoms, including 8% of patients who show no improvement or worsening.301 A patient's prior history of response to antipsychotic therapy for an acute episode generally is a reliable predictor of response to a subsequent trial.301

Long-term efficacy of antipsychotic agents generally has been established in terms of reductions in relapse (i.e., recurrence of acute episodes) or rehospitalization rates over a course of several years.301 More recently, long-term efficacy also has been measured in terms of quality of life, health services utilization, and social and vocational functioning.301 In addition, these outcome measures have been used to define level of patient recovery.301

The choice of an antipsychotic agent should be individualized, taking into consideration past response to therapy, adverse effect profile (including the patient's experience of subjective effects such as dysphoria), and the patient's preference for a specific drug, including route of administration.301

The American Psychiatric Association (APA) considers certain atypical (second-generation) antipsychotic agents (i.e., aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone) first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial.301 The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients.301 Conventional antipsychotic agents may be considered first-line in patients experiencing acute psychotic episodes who have been treated successfully in the past with, or who prefer, conventional agents.301

To compare the long-term effectiveness and tolerability of older, first-generation antipsychotic agents (i.e., perphenazine) with those of newer, atypical antipsychotic agents (i.e., olanzapine, quetiapine, risperidone, ziprasidone), a double-blind, multicenter study (Clinical Antipsychotic Trials of Intervention Effectiveness; CATIE) was sponsored by the National Institute of Mental Health.331 More than 1400 patients with schizophrenia received one of the drugs for up to 18 months or until therapy was discontinued for any reason.331 Patients with tardive dyskinesia could enroll in this trial; however, the randomization scheme prevented their assignment to the perphenazine group. The primary outcome measure in this study was the discontinuance of treatment for any cause; this measure was selected because discontinuing or switching an antipsychotic agent occurs frequently and is an important problem in the management of schizophrenia.331 In addition, this measure integrates the patient's and clinician's judgments concerning efficacy, safety, and tolerability into a more comprehensive measure of effectiveness reflecting therapeutic benefits in relation to adverse effects.331,332 Overall, 74% of patients in this study discontinued their medication before receiving the full 18 months of therapy because of inadequate efficacy, intolerable adverse effects, or for other reasons, suggesting substantial limitations in the long-term clinical effectiveness of currently available antipsychotic agents.331 Olanzapine appeared to be slightly more effective than the other drugs evaluated in this study with a lower (64%) discontinuance rate and a lower rate of hospitalization for exacerbation of schizophrenia, while no significant differences between the effectiveness of the conventional agent, perphenazine, and the other second-generation agents studied were observed (discontinuance rates were 75, 82, 74, and 79% for perphenazine, quetiapine, risperidone, and ziprasidone, respectively).331,334 Although there were no significant differences in the time until discontinuance of therapy because of drug intolerance among the drugs studied, the incidences of discontinuance for certain adverse effects differed among the drugs with olanzapine discontinued more frequently because of weight gain or metabolic effects (e.g., increases in glycosylated hemoglobin, cholesterol, and triglycerides) and perphenazine discontinued more frequently because of adverse extrapyramidal effects.331

Emerging data from the pivotal CATIE trial suggest that newer, atypical antipsychotics may not provide clinically important advantages over older, first-generation antipsychotics in patients with chronic schizophrenia and that several factors, including adequacy of symptom relief, tolerability of adverse effects, and cost of therapy, may influence a patient's ability and willingness to remain on long-term antipsychotic medication.331,332,333,334 In addition, these results suggest that it may often be necessary to try 2 or more different antipsychotic agents in an individual patient in order to provide optimal therapeutic benefit with an acceptable adverse effect profile.331,332,333,334

Pending further data clarifying the relative effectiveness and tolerability of first- and second-generation antipsychotics in the treatment of schizophrenia, many clinicians recommend that the choice of an antipsychotic agent be carefully individualized taking into consideration the clinical efficacy and adverse effect profile (including the risk for extrapyramidal effects, weight gain, and adverse metabolic effects) of the antipsychotic agent as well as individual patient risk factors; the patient's previous experience of subjective effects such as dysphoria; the patient's preference for and willingness to take (i.e., compliance) a specific drug, including route of administration; and the relative cost of therapy.301,331,332,333,334 Clozapine and olanzapine may be reasonable alternatives in any patient with schizophrenia who has not achieved a full clinical remission with other antipsychotic agents; however, the risk of adverse metabolic effects with both drugs necessitates dietary and exercise counseling before therapy is initiated, monitoring during drug therapy, and possible discontinuance of therapy if these effects become troublesome during therapy.301,331,332 Additional analyses from data generated by the CATIE trial addressing other schizophrenia treatment-related issues such as cost-effectiveness of therapy, quality of life, and predictors of response are ongoing.333,334

Some evidence suggests that atypical antipsychotic agents may have superior efficacy in treating cognitive, negative, and mood symptoms as well as global psychopathology, but this is controversial and remains to be fully established.301 Currently there is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although clinically meaningful differences in response may be observed in individual patients.301

Differences in risk of certain adverse effects are often predictable based on the potencies and receptor binding profiles of the various antipsychotic agents.301 When first-generation (conventional) antipsychotic agents are used, high-potency (e.g., haloperidol, fluphenazine) rather than conventional low-potency (e.g., chlorpromazine, thioridazine) antipsychotic agents often are selected initially despite their greater tendency to cause extrapyramidal reactions because their adverse effects often are easier to manage than the sedation, lethargy, and orthostatic hypotension associated with low-potency agents, and their dosage generally can be escalated more rapidly if necessary.301 However, a first-generation (conventional) antipsychotic agent of intermediate potency (e.g., loxapine, perphenazine) may be preferable in some patients, such as those who have difficulty tolerating extrapyramidal reactions (e.g., akathisia) from a high-potency agent and daytime drowsiness, dizziness, dry mouth, and constipation from a low-potency agent.301,329

The route of administration that is preferred also should be considered in the selection of an antipsychotic agent.301 Although many patients prefer oral therapy, patients with recurrent relapses related to nonadherence or those who prefer injectable formulations are candidates for a long-acting injectable antipsychotic agent (e.g., fluphenazine decanoate, haloperidol decanoate, risperidone).301 In such patients, an oral formulation of the same antipsychotic agent is a logical choice for initial therapy during the acute phase of schizophrenia.301 Although the transition from an oral to a long-acting injectable formulation may begin during the acute phase, long-acting injectable agents usually are not initiated for acute psychotic episodes because steady-state plasma drug concentrations are not achieved for several months, and they are eliminated very slowly.301 However, in some circumstances (e.g., continued therapy with a long-acting injectable agent while temporarily supplementing it with an oral agent during an exacerbation of psychotic symptoms), a long-acting (depot) antipsychotic preparation may be useful during an acute psychotic episode.301

When improvement is not observed in patients receiving an antipsychotic agent, nonadherence, rapid drug metabolism, or poor drug absorption should be considered.301 In patients receiving an antipsychotic agent with adequately described clinical pharmacokinetics (e.g., clozapine, haloperidol), measurement of plasma concentrations of the drug may be useful in determining whether the dosage is insufficient for efficacy or excessive and inducing adverse effects such as akathisia, agitation, or akinesia; whether the pharmacodynamics of the drug are affected by concurrent therapy with other drugs, young or old age, or comorbid condition; or whether adherence with therapy is inadequate.301,329 If nonadherence is suspected, behavioral tailoring (i.e., fitting medication administration into the patient's daily routine, psychotherapeutic techniques) may aid in the patient's understanding of the potential benefits of drug therapy.301 If surreptitious nonadherence (i.e., cheeking) is suspected, use of a liquid (e.g., clozapine, haloperidol, risperidone), rapidly disintegrating tablet (e.g., olanzapine, risperidone), or a short-acting IM formulation (e.g., haloperidol, ziprasidone) may be beneficial.301 In patients who do not respond to therapy despite adherence and adequate plasma concentrations of the drug, consideration should be given to alternative therapy.301 Increasing the dosage for a limited period (e.g., 2-4 weeks) can be attempted if tolerated by the patient.301 Failure of this alternative should lead to consideration of therapy with a different antipsychotic agent.301

Adjunctive agents (e.g., benzodiazepines) are commonly added to antipsychotic drug therapy during the acute phase to treat comorbid conditions or associated symptoms (e.g., agitation, aggression, affective symptoms), to address sleep disturbances, or to treat adverse effects associated with antipsychotic agents.301 For patients with treatment-resistant schizophrenia or with persistent suicidal or aggressive behavior or hostility, a trial of clozapine should be considered, based on evidence of superior efficacy in such patients.301 Other than clozapine, limited options exist for many patients who have substantial residual symptoms even after optimization of antipsychotic monotherapy.301 Although efficacy data are limited, various augmentation strategies have been used, including addition of another antipsychotic agent or other psychoactive agents (e.g., anticonvulsants, benzodiazepines, glutamatergic agents, cholinergic agonists).301 ECT and cognitive behavior therapy techniques also may be useful in patients with treatment-resistant symptoms.301

Because thioridazine and mesoridazine (no longer commercially available in the US) have the potential for substantial and possibly life-threatening proarrhythmic effects and can precipitate sudden death, use of these drugs is reserved for patients with schizophrenia whose disease fails to respond adequately to appropriate courses with at least 2 different antipsychotic agents, either because of insufficient efficacy or the inability to achieve an effective dosage due to intolerable adverse effects. 306,307,309,312,313,314 (See Cautions: Arrhythmias and Associated Precautions and Contraindications, in Thioridazine 28:16.08.24.)

Stabilization Phase

In patients who have achieved an adequate therapeutic response and minimal adverse effects with a particular regimen, therapy with the same antipsychotic agent at the same dosage should be continued over the next 6 months.301 Therapy during the stabilization phase is empiric, both in terms of specific agent and dosage, and is based principally on the clinical observation that premature reduction of dosage or discontinuance of therapy may result in relatively rapid relapse.301 During the stabilization phase, assessment of ongoing adverse effects that may have developed during the acute phase also is essential, and drug therapy should be adjusted as necessary to minimize adverse effects that may lead to nonadherence and relapse.301

Stable Phase

The efficacy of antipsychotic therapy in preventing relapse should be considered relative to the severity of adverse effects, and, as feasible, residual symptoms should be addressed in planning the long-term management of stabilized patients.301 The risk of relapse in patients in the stable phase of schizophrenia is reduced substantially with first-generation (conventional) antipsychotic agents but not eliminated completely (e.g., up to 25-30% may still experience relapse during the first year of therapy).301,329 Recent evidence suggests that use of second-generation (atypical) antipsychotics may result in greater efficacy in relapse prevention, although it currently is not known if other factors such as increased treatment adherence or reduced adverse effects contribute to this increase in efficacy.301

During the stable phase of a psychotic episode, there currently is no reliable strategy to identify minimum effective antipsychotic dosages for prevention of relapse.301 However, clinicians should attempt to employ a dosage that minimizes adverse effects while remaining within the effective dosage range of the particular agent.301 In patients receiving first-generation (conventional) antipsychotic agents, therapy at a lower dosage (e.g., equivalent to 300-600 mg daily of chlorpromazine hydrochloride) may yield such benefits as improvement in adherence, better subjective state, and, possibly, better functioning.301 Evidence suggests that higher dosages (e.g., equivalent to a mean dosage of 5200 mg daily of chlorpromazine hydrochloride) usually are not more effective and increase the risk of subjectively intolerable adverse effects.301 However, potential advantages of a lower dosage should be considered relative to the somewhat greater risk of relapse and more frequent exacerbations of schizophrenic symptoms.301

Some clinicians suggest that following management of an acute episode and patient stabilization, attempts be made to reduce the antipsychotic dosage by approximately 20% every 6 months until a minimum maintenance dosage is achieved; minimum maintenance dosages as low as 2.5 mg of oral fluphenazine hydrochloride or haloperidol daily, 50 mg of haloperidol decanoate every 4 weeks, or 5 mg of fluphenazine decanoate every 2 weeks have been suggested.301 Strategies in which dosage of a first-generation (conventional) antipsychotic agent is gradually reduced until completely discontinued during the stable phase, and drug therapy is reinitiated only intermittently to target symptom exacerbations and avert anticipated exacerbations may substantially increase the risk of relapse, and therefore are, not recommended.301

Because most patients who develop schizophrenia are at very high risk for relapse in the absence of antipsychotic therapy, prudent long-term treatment options in patients with remitted first or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence.301 Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent.301 However, evidence suggests that continued drug therapy is associated with fewer relapses than targeted intermittent therapy and that intermittent treatment strategies may increase rather than decrease the risk of tardive dyskinesia.301 If antipsychotic therapy is to be discontinued, additional precautions should include slow, gradual dose reduction (e.g., 10% per month) over many months, more frequent visits, and use of early intervention strategies.301 Patients and their family and caregivers should be advised about early signs of relapse, and clinicians should collaborate with them to develop plans for action should such signs emerge.301

In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended, along with continued monitoring for manifestations of impending or actual relapse because risk of relapse in chronic schizophrenia, even in patients adherent to drug therapy, is approximately 30% per year.301 The treatment program should be designed to respond quickly to evidence of prodromal symptoms or behaviors or exacerbations of schizophrenic symptoms.301 Early use of supportive therapeutic techniques and a higher drug dose as indicated can be useful in reducing the likelihood of relapse and hospitalization.301 During prodromal episodes, more frequent treatment, monitoring, and support should be undertaken, and assertive outreach, including home visits, should be used when indicated.301

In patients with schizophrenic disorder who have associated depression, phenothiazines may be given concomitantly with a tricyclic antidepressant (e.g., amitriptyline). A combination of a phenothiazine with a tricyclic antidepressant also may be used for the management of moderate to severe anxiety and depression associated with psychotic disorders, psychoneurosis, or chronic physical illness. Phenothiazines also have been used in combination with a monoamine oxidase (MAO) inhibitor in patients with depression accompanied by anxiety, agitation, or panic. Because of potentiation and a lowered margin of safety, combinations of psychotherapeutic agents should be used with caution and only in patients with severe disorders. When combination therapy is required, the commercially available preparations containing a phenothiazine in combination with an antidepressant should not be used to initiate therapy. Dosage should initially be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio present in a commercially available combination, such a preparation may be used; however, when dosage adjustment is necessary, the drugs should be administered separately.

Pediatric Considerations

Schizophrenia in children and adolescents is classified according to the age at onset of symptoms.319 Schizophrenia developing in children prior to 13 years of age is referred to as very-early-onset schizophrenia or childhood-onset schizophrenia.319 Schizophrenia that develops in pediatric patients 13-18 years of age is referred to as early-onset schizophrenia.319 Very-early-onset schizophrenia is a poorly understood neurodevelopmental disorder, but data collected thus far from clinical studies, case reports, and clinical experience suggest that the pattern of response to antipsychotic agents in children and adolescents with schizophrenia is similar to that in adults.319,323 Because there are few published clinical studies in children and adolescents with schizophrenia, therapeutic recommendations for the management of schizophrenia mainly are based on extrapolation of demonstrated efficacy in adults and the likelihood that the disease course, pathophysiology, and drug activity are substantially similar between the 2 populations.319 The American Academy of Child and Adolescent Psychiatry (AACAP) states that many of the therapeutic recommendations for adult-onset schizophrenia are applicable for the treatment of children and adolescents with schizophrenia provided that developmental issues are addressed.319 The goal of therapy in early-onset or very-early-onset schizophrenia is to return the child to their premorbid level of functioning while also promoting the mastery of age-appropriate developmental tasks.319 Adequate treatment therefore requires a combination of drug therapy and psychosocial interventions, which may vary depending on the phase of illness.319

As with treatment of adult-onset schizophrenia, antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia in pediatric patients.319 Most clinical studies in children and adolescents with schizophrenia involved first-generation (conventional) antipsychotic agents (e.g., haloperidol, loxapine, thioridazine, thiothixene), and these agents are considered a reasonable choice for initial therapy.319,320,321,322 However, because of greater sensitivity of children to the sedative effects of low-potency antipsychotic agents (e.g., thioridazine), it has been suggested that high-potency antipsychotic agents (e.g., thiothixene), which are associated with less frequent sedation, may be preferred as initial therapy in some pediatric patients with schizophrenia.322 Second-generation (atypical) antipsychotic agents (e.g., olanzapine, risperidone) also may be appropriate for initial therapy in certain children and adolescents, but the role of these agents relative to conventional agents remains to be established, particularly regarding long-term safety and efficacy.319 Similar to treatment of schizophrenia in adults, the choice of an antipsychotic agent in children and adolescents with schizophrenia should be individualized, based on the agent's relative potency, potential adverse effects, and the patient's past response to therapy.319 Although the AACAP considers all antipsychotic agents (except clozapine) to have comparable antipsychotic effects, many clinicians consider atypical antipsychotic agents, with the exception of clozapine, the drugs of choice for the management of schizophrenia because such agents have been associated with a lower risk for extrapyramidal symptoms than conventional antipsychotic agents.319

Because treatment resistance in adults with schizophrenia is associated with an earlier age of onset, children and adolescents who develop the disorder before age 18 may be less likely to respond adequately to either conventional or atypical antipsychotic agents than adults with the disorder.319 Clozapine currently is the only antipsychotic agent with clearly demonstrated efficacy in the management of treatment-refractory schizophrenia in adults.319 Results of one limited, double-blind, randomized clinical study indicate that clozapine (mean final dosage: 176 mg daily) is superior to haloperidol (mean final dosage: 16 mg daily) in reducing both positive and negative symptoms of schizophrenia in children and adolescents with very-early-onset treatment-resistant schizophrenia.319,323 As reported in adults, however, maximal antipsychotic effects in schizophrenic children and adolescents may not be evident until after 6-9 months of clozapine therapy.323 Clozapine is not considered a first-line agent because of its substantial potential for adverse effects and is recommended only in patients who have failed to respond to adequate therapeutic trials (i.e., use of sufficient dosages over a period of 4-6 weeks) of at least 2 other antipsychotic agents (at least one of which is an atypical antipsychotic) and/or have experienced substantial adverse effects (e.g., tardive dyskinesia) while receiving other antipsychotic agents.301,319 (See Uses: Psychotic Disorders, in Clozapine 28:16.08.04.)

Use of long-acting (depot) preparations also should be limited in children and adolescents with schizophrenia because these agents have not been adequately studied in this population and because of the risks of adverse effects associated with long-term exposure to these drugs.319 The AACAP currently does not recommend use of depot preparations in children with very-early-onset schizophrenia (i.e., development of the disorder before 13 years of age) and states that these preparations should only be considered in schizophrenic adolescents with documented chronic psychotic symptoms and a history of poor medication compliance.319

Geriatric Considerations

In geriatric patients with schizophrenia, the approach to treatment is similar to that in younger adults, although age-related physiologic changes (e.g., reduced cardiac output, reduced glomerular filtration rate, possible reduction in hepatic metabolism, increased adipose content, receptor-site activity alterations, sensory deficits, cognitive impairment) may influence selection and dosage of an antipsychotic agent.301 Important considerations in selection of an antipsychotic agent in geriatric patients include the adverse effect profile, potential adverse interactions with the patient's current drug therapy or effects on concurrent physical illness, and the patient's previous response to the antipsychotic agent.301,329 The APA currently recommends second-generation (atypical) antipsychotic agents as first-line therapy in geriatric patients because of their substantially lower risk of extrapyramidal symptoms and tardive dyskinesia compared with first-generation (conventional) antipsychotic agents.301 However, geriatric patients, particularly those with reduced cardiac output, also may be more sensitive to some adverse effects associated with atypical agents (e.g., sedation, orthostatic hypotension, cardiac arrhythmia).301 The anticholinergic effects of antipsychotic agents also are a concern in geriatric patients because age-related decreases in cholinergic function may contribute to adverse effects such as urinary retention, confusion, and constipation or fecal impaction. 301 Although weight gain associated with some antipsychotic agents may be beneficial in frail or malnourished geriatric patients, cardiovascular disease or osteoarthritis may be aggravated in patients with preexisting conditions.301 In addition, increased prolactin concentrations associated with antipsychotic agents may compromise bone-mineral density and increase osteoporosis in geriatric patients.301 (See Cautions: Precautions and Contraindications.)

Depression is common and may be functionally disruptive in geriatric patients with schizophrenia.301 In such patients, a variety of antidepressant agents have been added to the treatment regimen.301

Psychotic symptoms, including delusions and hallucinations, and behavioral disturbances, including agitation and aggression, are common in patients with dementia (e.g., dementia of the Alzheimer's type).326,341,342,343,344,345 Antipsychotic agents are the only drugs currently available for the management of psychotic manifestations of dementia, and they are the most commonly used and best-studied drugs for the management of agitation in demented patients.326,341,342,343,344,345 However, the APA currently recommends that nonpharmacologic interventions be attempted before a trial of antipsychotic drug therapy and that the interventions attempted be guided by the patient's level of distress and the risk to the patient and caregiver.326 Antipsychotic drug therapy generally is reserved for patients who are distressed or when associated agitation, combativeness, or violent behavior places the patient or others in danger.326 Therapy for the management of psychosis and agitation associated with dementia should be reevaluated periodically to justify its continued use.326 There currently are limited data establishing efficacy of antipsychotic drug therapy for psychosis and agitation in demented patients beyond 8 weeks of follow-up, although clinical experience suggests that benefit extends for longer periods of treatment.326,341,343,344,345 The fact that psychosis and agitation may wax and wane or change in character as the dementing illness evolves should be considered and may prompt a modification or discontinuance of antipsychotic drug therapy.326

The goal of therapy for the management of psychosis and agitation in patients with dementia is to decrease psychotic manifestations (e.g., paranoia, delusions, hallucinations) and associated or independent agitation, screaming, combativeness, and/or violence and thereby increase the comfort and safety of patients and their families and caregivers.326,343 Antipsychotic agents have been studied extensively for the management of psychosis and agitation in patients with dementia and current evidence indicates that the drugs can provide modest improvement in behavioral manifestations; some evidence suggests that antipsychotic efficacy may be better for psychosis than for other manifestations.326,341,342,343,344,345 The Clinical Antipsychotic Trials of Intervention Effectiveness—Alzheimer's Disease (CATIE-AD) effectiveness trial, which evaluated several atypical antipsychotics (olanzapine, quetiapine, and risperidone) in patients with Alzheimer's disease and psychosis or agitated behavior, found that these drugs were more effective for certain dementia-associated symptoms, including anger, aggression, and paranoid ideation, although their adverse effects may limit their clinical utility.341,344 Dropout rates in efficacy studies of antipsychotic agents have generally been high, both because of intolerable adverse effects and poor response.326,344 Antipsychotic efficacy appears to be similar among available agents and therefore the choice of agent should be based on adverse effect profile and other patient considerations; to minimize adverse effects, the lowest possible effective dosage should be used.326,343

The US Food and Drug Administration (FDA) warns that geriatric patients with dementia-associated psychosis treated with conventional (first-generation) or atypical (second-generation) antipsychotic agents are at an increased risk of death.330,335,336,337,338 Analyses of 17 placebo-controlled trials (average duration of 10 weeks) revealed an approximate 1.6- to 1.7-fold increase in mortality among geriatric patients receiving atypical antipsychotic agents (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that in patients receiving placebo.330,335 Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.330 Because an increase in mortality was observed with atypical antipsychotics in all 3 chemical classes, this effect is considered to be related to the common pharmacologic effects of all atypical antipsychotic agents, including those that have not been specifically studied in patients with dementia. 330 Subsequently, two observational, epidemiological studies have indicated that, similar to atypical antipsychotic agents, treatment with conventional antipsychotic agents in geriatric patients may increase mortality; the causes of death were not reported in the first study and cancer and cardiac disease were the causes of death with the highest relative risk in the second study.335,336,337,338 However, the extent to which these findings of increased mortality in observational studies may be attributed to the antipsychotic agent as opposed to certain patient characteristics remains unclear.337,338 FDA currently advises clinicians that antipsychotic agents are not approved for the treatment of dementia-related psychosis.335,336 The FDA further advises clinicians that no drugs currently are approved for the treatment of patients with dementia-associated psychosis and that other management options should be considered in such patients.335,336 The decision whether to prescribe antipsychotic agents “off-label” in the treatment of dementia symptoms is left to the discretion of the clinician.336 For additional information on the use of antipsychotic agents for dementia-associated psychosis and other behavioral disturbances, see Geriatric Precautions under Cautions.

For further information on the use of atypical antipsychotic agents in patients with dementia-associated psychosis, see the individual monographs in 28:16.08.04.

Delirium

Antipsychotic agents, including phenothiazines, are used in the management of delirium.303 Delirium is principally a disturbance of consciousness, attention, cognition, and perception but also may affect sleep, psychomotor activity, and emotions.303 It is a common psychiatric illness among medically compromised patients, particularly hospitalized patients, and may be a harbinger of substantial morbidity and mortality.303 The prevalence of delirium in hospitalized medically ill patients ranges from 10-30%; in those who are elderly, delirium ranges up to 40%.303 Up to 25% of hospitalized cancer patients and 30-40% of hospitalized patients with acquired immunodeficiency syndrome (AIDS) develop delirium.303 Up to about 50% of postoperative patients develop delirium, and up to 80% of terminally ill patients develop it near death.303 Prodromal manifestations may progress to full-blown delirium over 1-3 days; the duration of delirium generally ranges from less than a week to more than 2 months, but typically does not exceed 10-12 days.303 Symptoms persist for up to 30 days or longer in up to 15% of patients, and frequently persist for longer than 1 month in geriatric patients.303 Although most patients recover fully, delirium may progress to stupor, coma, seizures, and death, particularly if untreated.303 Full recovery is less likely in geriatric patients and patients with AIDS, possibly because of underlying dementia in both populations.303

Underlying general medical conditions associated with delirium include CNS disorders (e.g., head trauma, seizures, postictal state, vascular or degenerative disease), metabolic disorders (e.g., renal or hepatic failure, anemia, hypoxia, hypoglycemia, thiamine deficiency, endocrinopathy, fluid or electrolyte imbalance, acid-base imbalance), cardiopulmonary disorder (myocardial infarction, congestive heart failure, cardiac arrhythmia, shock, respiratory failure), and systemic illness (e.g., substance intoxication or withdrawal, infection, cancer, severe trauma, sensory deprivation, temperature dysregulation, postoperative state).303 EEG abnormalities, mainly generalized slowing, have fairly good sensitivity for aiding in the diagnosis of delirium, but the absence of such changes does not rule out the diagnosis.303

Clinicians should undertake an essential array of psychiatric management tasks designed to provide immediate interventions for urgent general medical conditions, identify and treat the etiology of delirium, ensure safety of the patient and others in contact with the patient, and improve the patient's functioning.303 Environmental (e.g., varying light levels in intensive care units to heighten awareness about time of day and reduce the perception of timelessness) and supportive interventions (e.g., to deal with disorientation, to assure the patient that manifestations are temporary and reversible and do not reflect a persistent psychiatric disorder) also generally are offered to patients with delirium and are designed to reduce factors that may exacerbate delirium, to reorient patients, and to provide support.303 Patients may have life-threatening medical conditions that require therapeutic intervention even before a specific or definitive cause of the delirium is determined.303 The goal of diagnosis is to identify potentially reversible causes of delirium and prevent complications through prompt treatment of these specific disorders.303 Psychiatric management is essential and should be undertaken for all patients with delirium.303 Somatic interventions principally consist of drug therapy.303 The choice of somatic intervention will depend on the specific features of the patient's clinical condition, the underlying etiology of the delirium, and any associated comorbid conditions.303

Antipsychotic agents often are the drugs of choice for the management of delirium.303 Although phenothiazines have been used, haloperidol (a butyrophenone) generally is considered the antipsychotic of choice for most patients with delirium because of its relatively low risk of anticholinergic activity and of sedative and hypotensive effects.303 In addition, haloperidol has been studied most extensively, although few studies have used standardized definitions of delirium or reliable and valid delirium symptom rating measures to assess symptom severity before and after initiation of treatment.303 For drugs other than haloperidol, there have been no large, prospective studies that included a control.303 Evidence of efficacy for such alternative therapies, including for relatively new second-generation (atypical) antipsychotic agents (e.g., olanzapine, quetiapine, risperidone), is principally from small case series or case reports.303 In addition, interpretation of findings from many such case presentations is difficult because of use of nonstandardized delirium definitions and/or informal measures of delirium symptom severity.303 In general, evidence of the efficacy of antipsychotics, including haloperidol, in the management of delirium comes from numerous case reports and uncontrolled studies.303 However, evidence from a randomized, double-blind, comparator-drug controlled study (chlorpromazine, haloperidol, and lorazepam) in patients with AIDS that employed standardized clinical measures of delirium demonstrated clinical superiority of antipsychotic agents compared with benzodiazepines.303,304 Statistically significant improvement in the Delirium Rating Scale was evident after 2 days in patients receiving chlorpromazine or haloperidol but not in the lorazepam group (mean decreases in the score [i.e., improvement] were 8.5, 8, and 1, respectively).303,304 The symptomatic improvement in delirium occurred quickly among patients receiving antipsychotic therapy, usually before initiation of interventions directed at the medical etiologies of delirium.303

Although various antipsychotic agents may be given orally, IM, or IV, IV administration is considered most effective in emergency situations or where oral access is limited.303 In addition, some evidence indicates that IV administration of antipsychotic agents may be associated with less severe extrapyramidal effects.303,305

Because antipsychotic agents used in the management of delirium have been associated with lengthening of the QT interval, possibly leading to atypical ventricular tachycardia (torsades de pointes), ventricular fibrillation, and sudden death, baseline and periodic ECGs should be performed with special attention paid to the length of the QT_c interval.303 Prolongation of the QT_c interval to greater than 450 msec or to greater than 25% over that in previous ECGs may warrant telemetry, a cardiology consultation, and dose reduction or discontinuance.303 Serum concentrations of magnesium and potassium also should be monitored in critically ill patients, especially those with baseline QT_c intervals of 440 msec or longer, those receiving other drugs known to increase the QT interval, and those who have electrolyte disorders.303

Other Psychoneurologic Disorders

Phenothiazines have been used for the management of the manic phase of bipolar disorder. Because antipsychotic agents (e.g., chlorpromazine) appear to be more effective than lithium in initially controlling the increased psychomotor activity of mania, many clinicians initiate treatment of acute mania with lithium and an antipsychotic agent. Once psychomotor activity has been controlled (usually within 3-7 days), the antipsychotic agent usually is tapered and lithium is continued to more specifically control disturbances of mood and ideation. Phenothiazines also have been used for the management of involutional, toxic, and senile psychoses.

Phenothiazines are used for the treatment of severe behavioral problems in children marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and for the short-term treatment of hyperactive children who exhibit excessive motor activity with accompanying conduct disorders that are manifested as impulsivity, difficulty sustaining attention, aggression, mood lability, and/or poor frustration tolerance. However, the possible risks of tardive dyskinesia, withdrawal dyskinesia, and other extrapyramidal reactions associated with the drugs should be considered.308 Some clinicians recommend routine administration of the Abnormal Involuntary Movement Scale (AIMS) to all children receiving antipsychotic agents for this indication.308

Some phenothiazines may be effective in controlling anxiety, tension, and agitation that occur in neuroses; however, the drugs may increase the severity of depression and do not appear to be effective in the treatment of patients with hysteria or obsessive-compulsive reactions. Further studies are needed to establish the efficacy of phenothiazines for their use in neuroses.

Phenothiazines have been used in the adjunctive treatment of alcohol dependence to reduce anxiety, tension, depression, and nausea and vomiting. Although phenothiazines have been used in the management of acute agitation associated with alcohol withdrawal, their efficacy has been equivocal; in addition, the safety of these drugs has been questioned in patients with alcoholic liver disease.

Emesis

Phenothiazines are used for the prevention and control of severe nausea and vomiting of various etiologies. The drugs are effective in the management of postoperative nausea and vomiting, and that caused by toxins, radiation, various drugs including cytotoxic agents, or disease (e.g., uremia, cancer, protracted migraine). In general, phenothiazines are not effective in preventing vertigo or motion sickness, or for the management of emesis caused by the action of drugs on the nodose ganglion or locally on the GI tract. Safe use of phenothiazines for the prevention and treatment of nausea and vomiting of pregnancy has not been established, and the manufacturers recommend that the drugs be used during pregnancy only when the potential benefits justify the possible risks to the fetus; some phenothiazines are contraindicated during pregnancy. (See Pregnancy, Fertility, and Lactation: Pregnancy, in Cautions.)

Other Uses

Some phenothiazines (e.g., chlorpromazine) are used for the treatment of intractable hiccups, acute intermittent porphyria, and as an adjunct in the treatment of tetanus.

Phenothiazines are also used to produce tranquilization and to reduce the incidence of nausea and vomiting in obstetrics and, in anesthesia and surgery, to reduce preoperative tension and anxiety, to permit smoother induction of anesthesia, to potentiate anesthetic agents (possibly lessening the danger of respiratory depression), and to reduce postoperative vomiting.

Some phenothiazines exert an antipruritic effect, especially in neurodermatitis and pruriginous eczema, and they may relieve psychogenic itching.

Administration

Phenothiazines may be administered orally, rectally, or by IM or IV injections; solutions of most phenothiazines are too irritating for subcutaneous injection. Phenothiazines should not be administered intra-arterially. IV administration of dilute solutions of phenothiazines may be accomplished by either fractional injection or slow infusion. IM injection should be made very slowly, deep into the upper outer quadrant of the gluteus maximus. IM injection of phenothiazines in geriatric patients who are thin or debilitated with reduced muscle mass should be avoided if possible because such injections may be painful, and absorption from the injection site may be erratic and unpredictable. Dilution of the commercially available injections with 0.9% sodium chloride injection or a local anesthetic such as 2% procaine hydrochloride injection and massaging the site of injection may help to reduce pain following IM administration. Because of the possibility of hypotension, patients should be in a supine position at the time of parenteral administration of a phenothiazine and should remain so for at least 30-60 minutes following completion of the injection or infusion.

Dosage

There is a wide range of individual requirements for phenothiazine dosage, and dosage must be carefully adjusted according to individual requirements and response, using the lowest possible effective dosage. The initial dosage may be increased gradually according to the patient's tolerance and therapeutic response; dosage should be increased more gradually in debilitated, emaciated, or geriatric patients. After symptoms are controlled, dosage may be reduced gradually to a maintenance level. Weeks or months of treatment at optimum dosage levels may be necessary to produce maximum clinical improvement in patients with resistant mental and emotional disturbances. Relapses are less frequent when chronically ill patients are kept on a prolonged maintenance dosage. However, because of the risk of adverse reactions associated with cumulative effects of phenothiazines, patients with a history of long-term therapy with phenothiazines and/or other antipsychotic agents should be evaluated periodically to determine whether maintenance dosage could be decreased or drug therapy discontinued. Dosage should not be terminated abruptly in those patients receiving high dosage for prolonged periods of time. (See Other Nervous System Effects in Cautions: Nervous System Effects.)

Acute Psychotic Episodes

Determination of the optimal dosage of an antipsychotic agent during an acute psychotic episode is complex because there usually is a delay between therapy initiation and full therapeutic response.301 An initial response to treatment may be apparent in 2-4 weeks, while a full or optimal response may take up to 6 months or longer.301 Generally, the optimal dosage of an antipsychotic agent is that which produces maximal therapeutic benefit and minimal adverse effects.301

In recent years, studies have consistently found that modest doses of first-generation (conventional) antipsychotic agents (e.g., haloperidol dosages less than 10 mg daily or plasma haloperidol concentrations less than 18 ng/mL) are as effective or more effective than higher dosages; moderate dosages have been reported to improve comorbid depression, while higher dosages are associated with greater risk of extrapyramidal effects and dysphoria.301 For most patients receiving first-generation (conventional) antipsychotic agents, the optimal dosage occurs at the “EPS threshold,” which is the dosage that will induce extrapyramidal effects but where minimal rigidity is observed upon physical examination of the patient.301 Atypical antipsychotic agents generally can be administered at dosages that are therapeutic but well below the EPS threshold.301

Dosage should be titrated as quickly as tolerated to the target dosage, and unless uncomfortable adverse effects become evident, patients should be monitored for 2-4 weeks before further increasing dosage or changing to another antipsychotic agent.301 Rapid dosage escalation beyond the target dosage should be avoided because it may create a false impression of increased efficacy, and higher dosages may actually be detrimental.301

Adverse effects of phenothiazines are numerous and may involve almost all organ systems. Some adverse effects may be attributed to the actions of the drugs on the central and autonomic nervous systems, whereas others are hypersensitivity reactions. Although all adverse reactions have not been reported with each individual phenothiazine, the possibility that they may occur should be considered. Some adverse reactions may occur more frequently and/or with greater intensity in patients with certain medical conditions (e.g., severe hypotension in patients with pheochromocytoma or mitral insufficiency).

Nervous System Effects

Extrapyramidal Reactions

Extrapyramidal reactions may occur in patients receiving phenothiazines and are apparently mediated via blockade of central dopaminergic receptors involved in motor function. More than 60% of patients receiving acute therapy with phenothiazines or other antipsychotic drugs develop clinically important extrapyramidal reactions in one form or another; some patients may develop more than one form at the same time.301

Extrapyramidal reactions can be divided into acute and chronic reactions. Acute extrapyramidal reactions are signs and symptoms that develop during the first days and weeks of phenothiazine or other antipsychotic agent administration, are dose related, and are reversible upon dosage reduction or discontinuance of the drug. However, severe extrapyramidal reactions have reportedly occurred even at relatively low dosages. Chronic extrapyramidal reactions are signs and symptoms that occur following months or years of therapy with phenothiazines or other antipsychotic drugs, are not clearly dose related, and may persist following drug discontinuance.

Acute extrapyramidal reactions produced by phenothiazines are classified into 3 major categories: dystonic reactions, feelings of motor restlessness (i.e., akathisia), and parkinsonian signs and symptoms.301 Chronic extrapyramidal reactions include tardive dyskinesia and tardive dystonia.301

Dystonic reactions and feelings of motor restlessness occur most frequently in young patients, especially those with acute infections or severe dehydration, whereas parkinsonian signs and symptoms predominate in geriatric patients, especially those with brain damage. Dystonic reactions usually occur rather early during treatment, but the incidence of feelings of motor restlessness and parkinsonian signs and symptoms is greater after several weeks of therapy. Phenothiazines that are most effective as antiemetics and those that are the most potent on a weight basis have been associated with the greatest incidence of extrapyramidal reactions. In general, propylamino derivatives of phenothiazine are most likely to induce parkinsonian signs and symptoms, whereas propylpiperazine derivatives are most likely to cause dystonic reactions.

Dystonic reactions usually are sudden in onset, are dramatic in appearance, and may cause great distress to the patient but generally respond dramatically to treatment. The reactions are characterized by spastic contraction of discrete muscle groups and may include spasm of the neck muscles, sometimes progressing to acute, reversible torticollis; extensor rigidity of back muscles, sometimes progressing to opisthotonos; carpopedal spasm; trismus; mandibular tics; alteration of temporomandibular joint function; difficulty swallowing or talking; perioral spasms often with protrusion of the tongue; and oculogyric crisis. Dystonic reactions may be accompanied by profuse sweating, pallor, and fever. Risk factors include young age, male gender, use of high-potency agents, high doses, and IM administration. In most patients, acute dystonic reactions occur within 24-72 hours following initiation of therapy or an increase in dosage. Dystonic reactions usually subside within a few hours, and almost always within 24-48 hours following discontinuance of the drug. Most patients respond rapidly to treatment with an anticholinergic antiparkinsonian agent (e.g., benztropine, trihexyphenidyl) or with diphenhydramine. Short-term maintenance treatment with an oral anticholinergic antiparkinsonian agent may be used to prevent recurrence of acute dystonic reactions. If the dystonic symptoms are not controlled following administration of an antiparkinsonian agent or diphenhydramine, the etiology of the adverse neurologic effects should be reevaluated. In some patients, dystonic reactions (e.g., laryngospasm) can be dangerous and even life-threatening. Therefore, appropriate supportive therapy such as maintaining an adequate airway and hydration should be instituted, if necessary. If phenothiazine therapy is reinstituted, it should be at a reduced dosa however, if dystonic reactions occur in children or pregnant women, the drug should not be reinstituted.

Feelings of motor restlessness (akathisia) consist of agitation, jitteriness, inability to sit still, tapping of feet, strong urge to move around (not associated with anxiety), and sometimes insomnia; akathisia also may sometimes include a psychic component that is similar to the patient's original neurotic or psychotic symptoms. Patients with akathisia typically complain of an inner sensation of restlessness and an irresistible urge to move various parts of their body. Akathisia often is extremely distressing to patients, is a frequent cause of noncompliance with therapy, and, if allowed to persist, can produce dysphoria and possibly even contribute to aggressive or suicidal behavior. Akathisia is manifest subjectively and objectively in up to 30% of patients receiving conventional antipsychotic agents. Akathisia appears to occur less commonly with low-potency first-generation (conventional) antipsychotic agents and even less frequently with atypical antipsychotic agents than with other first-generation antipsychotic agents; however, precise estimates of akathisia incidence with individual agents currently are not available.

In most cases, akathisia occurs within 2-3 days of therapy, although it can occur later (i.e., after several weeks). Diagnosis of phenothiazine-induced akathisia may be difficult since signs and symptoms may resemble dyskinesias, Huntington's chorea, or exacerbation of the patient's underlying condition. Signs and symptoms of akathisia may subside spontaneously; however, if they become troublesome, interventions include dosage reduction or switching to an atypical antipsychotic agent with less risk of akathisia. Concomitant administration of low-dose propranolol or a benzodiazepine is effective in decreasing symptoms of akathisia, but anticholinergic antiparkinsonian agents have limited efficacy.

Parkinsonian Manifestations

Phenothiazine-induced parkinsonian signs and symptoms include masklike facies, drooling or hypersalivation, tremors, pill-rolling motion of the fingers, cogwheel rigidity, postural abnormalities, shuffling gait, slow monotonous speech, and dysphagia. Akinesia or bradykinesia may also occur. Symptoms of phenothiazine-induced parkinsonism, particularly the cognitive and emotional features, should be carefully distinguished from the negative symptoms of schizophrenia. The first approach to treatment of parkinsonian signs and symptoms should be reduction in the phenothiazine dosage. If symptoms are not sufficiently improved after reduction in phenothiazine dosage, a switch to an atypical antipsychotic agent should be considered. Although anticholinergic antiparkinsonian agents or dopamine agonists (e.g., amantadine) often reduce the severity of parkinsonian symptoms, anticholinergic agents can cause anticholinergic adverse effects and dopamine agonists may exacerbate psychosis; thus, chronic use and excessive dosages of such agents should be minimized or avoided. In most patients, concomitant administration of an antiparkinsonian agent for a few weeks to 2 or 3 months is adequate.

Because of the high risk of acute extrapyramidal reactions in patients receiving phenothiazines and other antipsychotic drugs, the prophylactic use of anticholinergic antiparkinsonian agents may be considered.301 Although such prophylaxis has been shown to reduce the incidence of acute extrapyramidal adverse effects, routine prophylaxis with antiparkinsonian agents in all patients generally is not recommended because it may be clinically unnecessary and associated with bothersome adverse effects.301 However, minimizing uncomfortable, painful, and unnecessary adverse effects can contribute substantially to establishing a therapeutic alliance between the clinician and the patient.301 Some authorities recommend that prophylaxis be considered for patients with a previous history of acute extrapyramidal reactions and those receiving antipsychotic agents known to induce these effects (e.g., first-generation [conventional] antipsychotics, high-dose risperidone).301 In addition, young patients experiencing their first episode of schizophrenia also may be considered for prophylaxis with an anticholinergic antiparkinsonian agent since they are more likely to experience dystonic reactions.301 The continued need for prophylaxis should be reevaluated after the acute phase of treatment is complete and whenever the dosage of the antipsychotic agent is changed.301 If antipsychotic dosage is lowered, anticholinergic prophylaxis may no longer be necessary or may be given in a lower dosage.301 Patients who are very sensitive to adverse anticholinergic effects (e.g., dry mouth, blurred vision, constipation) may require lower dosages of the antiparkinsonian agent or a less potent drug (e.g., trihexyphenidyl, procyclidine hydrochloride).301

Tardive Dyskinesia

Like other first-generation (conventional) antipsychotic agents, phenothiazines have been associated with persistent dyskinesias. The risk of tardive dyskinesia appears to be substantially less with second-generation (atypical) antipsychotics than with first-generation agents. Tardive dyskinesia may occur in some patients during long-term administration of the drugs or it may occur following discontinuance of the drugs. The risk of developing tardive dyskinesia appears to be greater in geriatric patients receiving high dosages of the drugs, especially females. Other possible risk factors include schizophrenia, presence of antipsychotic-induced parkinsonian symptoms, concurrent affective disorder, and concurrent medical conditions (such as diabetes mellitus). The symptoms are persistent and in some patients appear to be irreversible. Tardive dyskinesia is characterized by rhythmic involuntary movements of the tongue, face, mouth, or jaw (e.g., protrusion of the tongue, puffing of cheeks, chewing movements, puckering of the mouth), which sometimes may be accompanied by involuntary movements of the extremities. Although the majority of patients who develop tardive dyskinesia have mild symptoms, approximately 10% develop symptoms that are moderate to severe. Tardive dystonia, an often severe variant of tardive dyskinesia, is characterized by spastic muscle contractions and associated with severe distress and physical discomfort. Although not clearly established, the risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with the duration of therapy and cumulative dose of antipsychotic agent(s) administered; however, the syndrome may occur, although much less frequently, after relatively short periods of treatment with low dosages. In addition, although continued therapy may increase the risk of persistence of tardive dyskinesia symptoms, the severity of tardive dyskinesia does not appear to increase over time in many patients receiving constant, moderate dosages. In clinical studies, intermittent, targeted treatment with a first-generation (conventional) antipsychotic agent was associated with an increased risk of tardive dyskinesia compared with that observed with maintenance antipsychotic treatment.

Some clinicians recommend that patients receiving antipsychotic agents for prolonged periods (for more than 4 weeks) be evaluated every 3 months or more often, depending on the frequency of visits, for signs or symptoms of tardive dyskinesia. If such signs or symptoms are present, clinicians should carefully evaluate the patient to rule out potential idiopathic causes of tardive dyskinesia. This evaluation should include a standard neurologic evaluation, a review of the patient's family medical history for neurologic disease (e.g., Huntington's disease), and appropriate laboratory tests. Once idiopathic causes of tardive dyskinesia have been ruled out, the patient may be considered to have tardive dyskinesia, and treatment options should be considered. Discontinuance of the phenothiazine should be considered only if the patient is in full remission or very stable with few residual positive symptoms or if the patient insists on discontinuing medication. Clinicians should consider the possibility that tardive dyskinesia may be masked if therapy is reinstituted, dosage is increased, or therapy with another antipsychotic agent is initiated. The effect that masking of the symptoms may have on the long-term course of the syndrome is unknown. Fine vermicular movement of the tongue may be an early sign of tardive dyskinesia; prompt evaluation and treatment if this sign occurs may help to prevent further development of the syndrome.

Management of tardive dyskinesia generally consists of gradual discontinuance of the precipitating antipsychotic agent when possible, reducing the dosage of the first-generation (conventional) antipsychotic agent or switching to a second-generation (atypical) antipsychotic agent, or switching to clozapine therapy.301,400,401,403,404 For example, the dosage of the phenothiazine could be reduced gradually (i.e., over 12 weeks) by 50%; frequently, this will produce a decrease or remission in the tardive dyskinesia. However, a temporary increase in symptoms upon withdrawal or dosage reduction also may occur in some patients. If withdrawal or dosage reduction does not produce substantial improvement in the tardive dyskinesia symptoms within 6-12 months, then the severity and degree of distress the symptoms cause the patient should be evaluated. If the symptoms are mild or do not cause the patient distress, then no further measures may be clinically necessary. However, treatment for tardive dyskinesia should be considered if the symptoms are severe or distressing to the patient.

Vesicular monoamine transporter 2 (VMAT2) inhibitors, including deutetrabenazine, tetrabenazine†, and valbenazine tosylate, have been shown to be effective in reducing symptoms of tardive dyskinesia in controlled clinical studies.400,401,403,404,405,408,409 Deutetrabenazine and valbenazine tosylate currently are indicated in the treatment of tardive dyskinesia.405,407 (See Deutetrabenazine 28:56 and Valbenazine Tosylate 28:56.) Although tetrabenazine, which is labeled for the treatment of chorea associated with Huntington's disease,401,404,406,408 had been considered a drug of choice by some clinicians for the management of moderate to severe tardive dyskinesia, the drug's short elimination half-life and dose-related adverse effect profile have limited the clinical use of the drug for tardive dyskinesia.400,401,404

Although long-term prospective incidence studies are lacking, clozapine generally has been shown to improve the severity of dyskinetic movements compared with conventional antipsychotic agents in controlled short-term and long-term studies.301,403 Various other agents have been evaluated as possible treatment for tardive dyskinesia (e.g., amantadine†, benzodiazepines†, anticholinergic agents†, botulinum toxin†, calcium channel-blocking agents†, donepezil†, γ-aminobutyric acid agonists [baclofen, valproic acid]†, essential fatty acids, estrogen†, insulin†, lithium†, melatonin, propranolol†, pyridoxine), but their clinical efficacy remains unproven.301,400,403,404 Because some evidence suggests that vitamin E may decrease the risk of developing tardive dyskinesia and because there is a low risk of adverse effects associated with the drug,301,401 some clinicians recommend vitamin E (400-800 units daily) as prophylactic therapy.301

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) may occur in patients receiving phenothiazine or other antipsychotic therapy. NMS has been characterized by hyperthermia, severe extrapyramidal dysfunction (including severe hypertonicity of skeletal muscles), varying levels of consciousness (including stupor and coma), altered mental status (including catatonic reactions), and autonomic instability (including cardiovascular effects such as hypertension and tachycardia). Autonomic effects often include pallor, diaphoresis, alterations in blood pressure, tachycardia, and cardiac arrhythmias. Motor abnormalities often include akinesia and rigidity. Increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, rhabdomyolysis (evidenced by myoglobinuria), acute renal failure, and leukocytosis also may occur.

NMS appears to be a relatively uncommon adverse effect of phenothiazines, but the syndrome can be sudden and unpredictable in its onset, frequently is misdiagnosed, and can be fatal in 5-20% of cases if left untreated. The syndrome usually occurs early in the course of therapy with phenothiazines or other antipsychotics, often within 1 week after treatment is initiated or dosage is increased. NMS may not recur with rechallenge. The syndrome appears to occur more frequently in young men, and predisposing factors may include acute agitation, heat stress, physical illness, dehydration, concurrent organic brain disease or other neurologic disability, rapid escalation of dose, use of high-potency agents, and use of an intramuscular preparation. NMS appears to progress rapidly over 24-72 hours after initial manifestations occur, although a more insidious progression has also been described. When the syndrome is fatal, death generally occurs 3-30 days after onset and may result from cardiac arrhythmias, cardiovascular collapse, respiratory failure, thromboembolism, aspiration pneumonia, and/or rhabdomyolysis with acute renal failure.

Treatment of NMS includes immediate discontinuance of phenothiazine therapy and initiation of supportive and symptomatic therapy, including correction of fluid and electrolyte imbalances, cooling of the patient, maintenance of renal function, management of cardiovascular instability (e.g., stabilizing blood pressure), and prevention of respiratory complications. Some case series suggest that treatment with a dopamine agonist (e.g., bromocriptine, amantadine) or dantrolene may improve symptoms of NMS when compared with supportive treatment alone. Treatment with benzodiazepines (e.g., lorazepam) also may be helpful, based on the overlap in symptoms between catatonia and NMS. Electroconvulsive therapy (ECT) has been reported to improve symptoms in patients with severe and resistant NMS. Recovery generally occurs within 5-10 days after discontinuance of the phenothiazine, but may be substantially prolonged following discontinuance of long-acting depot preparations. Irreversible CNS damage may occur. Some clinicians suggest that, if psychotropic therapy is reinstituted following recovery, alternative therapies should be considered. If the benefit of antipsychotic therapy is thought to outweigh the risk, extreme caution and careful monitoring should be exercised and second-generation (atypical) or low-potency, first-generation (conventional) agents should be used with gradual increases in dosage, if possible. Additional experience is necessary, but the risk that NMS can recur must be considered.

Other Nervous System Effects

Drowsiness, which is usually mild to moderate in severity, occurs frequently, particularly during the first weeks of therapy with some phenothiazines; however, tolerance to the sedative effect usually develops in most patients over a period of days or weeks during long-term administration. Although sedation is more common with low-potency, first-generation agents (such as chlorpromazine), it occurs to some extent with all phenothiazines. In agitated patients, the sedating effects of phenothiazines during initial therapy can be beneficial. However, sedation that persists during maintenance therapy and causes daytime drowsiness and increased sleep time can interfere with social, vocational, and recreational function. In such cases, a reduction in the daily dosage, administration of the entire daily dosage as one evening dose, or a switch to a less sedating (i.e., higher potency) phenothiazine or another antipsychotic agent can be helpful. Although there are no systematic data regarding specific pharmacologic interventions for sedation, some clinicians consider caffeine a relatively safe treatment option. Wakefulness-promoting agents (e.g., modafinil) also have been used to treat daytime drowsiness. Other adverse nervous system effects of phenothiazines include insomnia, restlessness, anxiety, euphoria, agitation, depression, weakness, headache, and cerebral edema.

Seizures may occur in patients receiving phenothiazines or other antipsychotic agents, particularly in patients with EEG abnormalities or a history of such disorders. Low-potency conventional antipsychotic agents and clozapine appear to be associated with the highest risk of seizures. The incidence of seizures is dose related and incidences generally are less than 1% for conventional antipsychotic agents when given in the usual recommended dosage range, although patients with a history of idiopathic or drug-induced seizures have an increased risk. If a patient receiving a phenothiazine or other antipsychotic agent (except clozapine) experiences a seizure, some authorities recommend the drug be withdrawn or the dosage reduced by 50% until a neurologic examination can be completed. Exacerbation of psychotic symptoms and catatonic-like behavior, which may subside following discontinuance of therapy or treatment with anticholinergic agents, also has been reported. Abnormality of the CSF proteins also has been reported.

Adverse anticholinergic effects of phenothiazines include dry mouth (xerostomia), blurred vision, mydriasis, constipation, obstipation, nausea, adynamic ileus, atonic colon, urinary retention, decreased sweating, and impotence (difficulty achieving and maintaining an erection). Dryness of the mouth may make retention of full dentures difficult. Although most anticholinergic adverse effects are mild and tolerable, these effects can be troublesome in older patients (e.g., older men with benign prostatic hypertrophy). The incidence and severity of adverse anticholinergic effects may be increased by concomitant administration of anticholinergic antiparkinsonian agents, antidepressants, and other drugs with marked anticholinergic activity. Adverse anticholinergic effects are usually dose related and may improve with dosage reduction or administration of the anticholinergic antiparkinsonian agent in divided doses. Parenteral physostigmine has been used to reverse the symptoms of anticholinergic delirium; however, it has resulted in serious adverse effects, including seizures, bronchospasm, and severe bradyarrhythmias, when given to patients with tricyclic antidepressant overdosage and other forms of anticholinergic toxicity.346,347,348,349,350,352,353,354,355 Therefore, most clinicians caution against the routine use of physostigmine in patients with anticholinergic manifestations.346,347,348,349,350,352,355

Phenothiazines depress the hypothalamic mechanism for regulation of body temperature and, depending on the environmental temperature, may cause hyperthermia and heat prostration, or hypothermia and respiratory distress. Hypothermic collapse has been reported in patients swimming in cold water.

Phenothiazines are not associated with psychic dependence and do not produce tolerance or addiction; however, some symptoms resembling physical dependence such as gastritis, nausea and vomiting, dizziness, tremulousness, feeling of warmth or cold, sweating, tachycardia, headache, and insomnia have occurred following abrupt withdrawal in some patients receiving prolonged maintenance therapy with phenothiazines. These symptoms can usually be avoided, or their severity reduced, by gradual withdrawal of the drugs or by continuing concomitant anticholinergic antiparkinsonian agents for several weeks following discontinuance of phenothiazines.

Cardiovascular Effects

Hypotension (including postural hypotension), tachycardia, increased pulse rate, syncope, and dizziness have occurred in patients receiving phenothiazines, especially with low-potency phenothiazines and following the first parenteral dose of a phenothiazine, but rarely after the first oral dose. These cardiovascular effects usually subside within 30-120 minutes; occasionally they may be more severe and prolonged, resulting in a shock-like syndrome. Tolerance to the hypotensive effects of the drugs usually develops. Marked hypotension occurs infrequently, and hypotension severe enough to cause fatal cardiac arrest has occurred rarely. Hypotension occurs most frequently when phenothiazines are given parenterally; therefore, patients should be in a supine position at the time of parenteral administration and should remain so for at least 30-60 minutes following completion of the injection or infusion. Patients who experience postural hypotension should be cautioned not to get up quickly and to obtain assistance when necessary. Hypotension may be a particular problem in patients with pheochromocytoma or mitral insufficiency, and severe hypotension has occurred with usual dosages in these patients. The management of antipsychotic-induced hypotension may include a variety of measures such as the use of support stockings, an increase in dietary salt intake, and/or fludrocortisone therapy. Severe hypotensive effects may be alleviated by the administration of norepinephrine or phenylephrine; epinephrine should not be used because phenothiazines cause a reversal of epinephrine's vasopressor effects and a further lowering of blood pressure.

Various ECG changes, including nonspecific, usually reversible, Q- and T-wave abnormalities have occurred in some patients receiving phenothiazines. (See Uses: Delirium.) ECG changes may resemble quinidine-like alterations or those induced by hypokalemia. Sudden death, apparently secondary to cardiac arrest, also has occurred.

Thioridazine and Mesoridazine

Dose-related serious cardiac effects, including prolongation of the QT interval corrected for rate (QT_c), arrhythmias (e.g., atypical ventricular tachycardia [torsades de pointes]), and/or sudden death, have been reported in patients receiving thioridazine or mesoridazine (no longer commercially available in the US).306,312,313,314 A causal relationship to the drugs has not been established; however, since both drugs have been shown to prolong the QT_c interval, such relationships are possible.307,312,313

Cardiotoxic effects may be associated with increased plasma concentrations of thioridazine and its metabolites (e.g., mesoridazine).312 Increased plasma concentrations of thioridazine are most likely to develop in patients with poor metabolizer phenotypes of the cytochrome P-450 (CYP) 2D6 isoenzyme and in patients receiving drugs known to inhibit the CYP2D6 isoenzyme (e.g., fluoxetine, paroxetine) or to reduce the clearance of thioridazine by other mechanisms (e.g., fluvoxamine, pindolol, propranolol).306,307,312 Patients with a history of cardiac arrhythmias and those with an underlying condition that might prolong the QT_c interval (e.g., hypokalemia, bradycardia, congenital prolongation of the QT interval) or who are receiving drugs that might prolong the QT_c interval also may be at increased risk of developing cardiac arrhythmias (e.g., torsades de pointes) and/or sudden death if thioridazine or mesoridazine were used. Therefore, the indications and circumstances for use of these drugs has been reduced substantially relative to other antipsychotic agents, and both thioridazine and mesoridazine are now contraindicated in a variety of patients because of such underlying risk factors of existing drug therapy. (See Cautions: Precautions and Contraindications.)

For further information on the cardiotoxic effects of thioridazine, see Cautions: Arrhythmias and Associated Precautions and Contraindications, in Thioridazine 28:16.08.24.

Hematologic Effects

In clinical trial and/or postmarketing experience, leukopenia and neutropenia temporally related to antipsychotic agents have been reported.376,378,412,413 Agranulocytosis also has been reported.412,413,517,518,519

Possible risk factors for leukopenia and neutropenia include a preexisting low leukocyte count and a history of drug-induced leukopenia or neutropenia.412,413 Therefore, patients with a history of clinically important low leukocyte count or drug-induced leukopenia and/or neutropenia should have their complete blood count monitored frequently during the first few months of antipsychotic agent therapy.412,413 Discontinuance of the antipsychotic agent should be considered at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.412,413

Patients with clinically important neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs or symptoms occur.412,413 In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm³), the antipsychotic agent should be discontinued and the leukocyte count monitored until recovery occurs.412,413

Supportive therapy with biosynthetic hematopoietic agents, including filgrastim, a recombinant human granulocyte colony-stimulating factor (G-CSF), and sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), has been effective in a limited number of patients with clozapine- or chlorpromazine-induced neutropenia or agranulocytosis.507,508,509,510,511,512,513,514,515,516,517,518,519

Lithium reportedly has been used successfully in the treatment of several cases of leukopenia and neutropenia associated with aripiprazole, clozapine, olanzapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.376,378

Other reported adverse hematologic effects of phenothiazines include eosinophilia; thrombocytopenia; aplastic anemia with pancytopenia, purpura, or granulocytopenia; and hemolytic anemia.

Dermatologic Effects

Various dermatoses, often associated with pruritus and marked photosensitivity, may occur during treatment with phenothiazines. Photosensitivity occurs infrequently in patients receiving phenothiazines and other antipsychotic drugs and is most common with the low-potency phenothiazines. Patients should be instructed to avoid excessive sunlight and/or to apply sunscreen and wear protective clothing. Other adverse dermatologic effects include urticaria, erythema, eczema, and exfoliative dermatitis. In general, dermatologic reactions have been reported most frequently in patients receiving propylamino or alkylpiperidine derivatives of phenothiazine. Contact dermatitis, usually of the erythematous or eczematous type, has occurred rarely.

Long-term administration of high doses of phenothiazines may result in pigment depositions in various body tissues. Pigmentary changes of the skin are generally restricted to exposed areas of the body, and exposure to light appears to be a contributing factor. The skin is usually yellowish-brown, but pigmentary changes range from an almost imperceptible darkening of the skin to greyish-purple. In some patients, histologic examination has revealed a pigment that is a melanin-like complex and that usually occurs in the dermis. The pigment may also be widely distributed into the brain, heart, liver, kidneys, retina, and cornea. Pigmentation may fade following discontinuance of the drug. If pigmentary changes occur, it should be determined whether the potential benefits of continued therapy justify the possible risks, and whether therapy should be continued or withdrawn or dosage reduced.

Ocular Effects

Ocular changes including deposition of fine particulate matter in the lens and cornea have been reported in patients receiving high doses of phenothiazines for prolonged periods of time. Pigmentary retinopathy and corneal opacities may occur during chronic therapy with the low-potency phenothiazines chlorpromazine and thioridazine, particularly at high dosages. Ocular changes reportedly occur more frequently than skin pigmentation and have occurred in patients with or without phenothiazine-induced skin pigmentation. In more advanced cases, star-shaped opacities may occur in the anterior portion of the lens. In extreme cases, visual impairment may occur. Epithelial keratopathy, lacrimation, and pigmentary retinopathy have also been reported. It has been suggested that ocular lesions may regress following discontinuance of phenothiazines. Although the precise cause of these adverse ocular effects is not known, exposure to light along with high dosage of phenothiazines and prolonged duration of therapy appear to be contributing factors. If ocular changes occur, it should be determined whether the potential benefits of continued phenothiazine therapy justify the possible risks, and whether therapy should be continued or withdrawn or dosage reduced.

GI Effects

Adverse GI effects of phenothiazines include anorexia, dyspepsia, constipation, paralytic ileus, and, occasionally, diarrhea. The “oral syndrome” consisting of dryness of the mouth; diffuse redness of mucous membranes of the mouth; loosened dentures with or without vesicles in the mouth or on the tongue; denture stomatitis; cracking of the lips and corners of the mouth; white or black, hairy tongue or bald, beefy, red tongue; and thin, white pseudomembrane formation in the oral cavity has also been reported.

Endocrine and Metabolic Effects

All first-generation (conventional) antipsychotic agents increase serum prolactin concentrations. (See Cautions: Carcinogenicity.) The resultant hyperprolactinemia may lead to galactorrhea in approximately 1-5% of patients and menstrual cycle changes (e.g., oligomenorrhea) in up to 20% of women. Mastalgia and gynecomastia also have occurred in some patients. A reduction in dosage may alleviate or decrease the severity of these adverse effects or drug therapy may be switched to an antipsychotic with less effect on prolactin (e.g., any atypical antipsychotic except risperidone). In patients with severe galactorrhea or in women with menstrual disturbances but in whom the antipsychotic dosage must be maintained, the administration of a low dosage of bromocriptine (2-10 mg daily) or amantadine may be helpful. Increased appetite, hyperglycemia, hypoglycemia, glycosuria, and high or prolonged glucose tolerance curves also have occurred in some patients.

Weight gain occurs with most antipsychotic agents, including in up to 40% of patients treated with the first-generation (conventional) antipsychotic agents, with the greatest risk associated with low-potency agents.301 Molindone appears less likely than other agents in this class to produce weight gain.301 Because weight loss is difficult for many patients, prevention of weight gain is important. In the event that clinically important weight gain occurs during therapy, diet and exercise interventions should be suggested.301 However, if the clinical benefit of the antipsychotic agent does not outweigh the potential health risks of weight gain (e.g., cardiovascular disease, hypertension, cancers, diabetes, osteoarthritis, sleep apnea), a trial of an antipsychotic with a lower weight-gain liability should be considered.301

Phenothiazines may decrease urinary gonadotropin, estrogen, and progestin concentrations and decrease vasopressin and corticotropin secretion.

Genitourinary Effects

Adverse effects on sexual function may occur in patients receiving phenothiazines and other antipsychotic agents.301 Erectile dysfunction appears to be the most common adverse effect in male patients, reportedly occurring in approximately 20-50% of men receiving first-generation (conventional) agents.301 Other effects include ejaculatory disturbances in men, including delayed or absent ejaculation, and loss of libido and anorgasmia in both men and women.301 In addition, certain drugs, including thioridazine and risperidone, have been associated with retrograde ejaculation.301 Priapism also had occurred during phenothiazine therapy. Although not clearly established, these effects appear to result principally from the α-adrenergic- and serotonergic-blocking effects of these drugs.301 A reduction in dosage or discontinuance of therapy usually results in improvement or elimination of these symptoms; in some patients, a switch to another agent may be helpful.301 There is some evidence that imipramine (25-50 mg daily at bedtime) may be helpful in treating retrograde ejaculation in thioridazine-treated patients.301 In patients in whom a reduction in dosage or switch to an alternative drug is not feasible, yohimbine or cyproheptadine therapy could be considered; psychoeducation also may help patients tolerate this bothersome but not clinically dangerous adverse effect.301

Sensitivity Reactions and Hepatic Effects

Sensitivity reactions and adverse hepatic effects including cholestatic jaundice, elevated hepatic enzyme concentrations, blood dyscrasias, dermatoses, and photosensitivity generally occur within the first few months after initiation of phenothiazine therapy, but occasionally they may occur following discontinuance of the drug.

Cholestatic jaundice usually occurs within 2-4 weeks after initiation of therapy in approximately 0.1-4% of all patients receiving phenothiazines. Jaundice may also occur in neonates whose mothers have received phenothiazines during pregnancy. Phenothiazine-induced jaundice resembles infectious hepatitis, with laboratory features of obstructive jaundice rather than parenchymal damage, and the clinician should be alert to the signs of cholestatic jaundice, including upper abdominal pain, nausea, yellow skin, influenza-like symptoms, rash, fever, and abnormal laboratory findings such as eosinophilia, bile in the urine, and elevated serum bilirubin, alkaline phosphatase, and transaminase concentrations. If signs of jaundice occur, the drug should be discontinued immediately. Weekly urine bilirubin tests during the first month of therapy may detect the reaction and warrant discontinuance of phenothiazine therapy. However, because antipsychotic-induced cholestatic jaundice occurs infrequently, other possible causes of jaundice should be ruled out before attributing the jaundice to the antipsychotic agent. Although fatalities are rare and clinical recovery from jaundice usually occurs within a few weeks following discontinuance of the drug in most patients, results of liver function tests and biopsies indicate that histopathologic changes may persist for longer periods, and chronic jaundice has been reported in some patients. There is no conclusive evidence that preexisting liver disease increases the susceptibility to phenothiazine-induced jaundice.

Laryngeal edema, laryngospasm, bronchospasm, angioedema, and anaphylactoid reactions have occurred in patients receiving phenothiazines.

Contact dermatitis, usually of the erythematous or eczematous type, has been reported in persons who come in contact with solutions of certain phenothiazine derivatives; care should be taken to avoid getting solutions of these drugs on the hands or clothing. Photosensitivity has occurred. Other dermatologic effects of phenothiazines may also be sensitivity reactions to the drugs. (See Cautions: Dermatologic Effects.)

Other Adverse Effects

Hyperpyrexia, mild fever (following IM administration of large doses), diaphoresis, peripheral edema, and a systemic lupus erythematosus-like syndrome have occurred in patients receiving phenothiazines.

Sudden and unexpected deaths have occurred in patients receiving phenothiazines, especially during long-term administration of the drugs. In some patients, sudden death appeared to result from asphyxia (secondary to failure of the cough reflex) or cardiac arrest.

Precautions and Contraindications

Because of the risk of inducing serious, potentially irreversible adverse effects (see Cautions: Nervous System Effects), the clinical need for phenothiazine and/or other antipsychotic therapy should be established, especially when prolonged therapy with the drugs is anticipated. The likelihood of some effects (e.g., tardive dyskinesia) becoming irreversible may increase with the duration of therapy and cumulative dose of antipsychotic agent(s) administered. Therefore, long-term therapy with antipsychotic drugs generally should be reserved for patients with a chronic disorder known to be responsive to these drugs and for which alternative, equally effective, but potentially less toxic therapy is not available or appropriate. In patients requiring long-term antipsychotic therapy, the smallest effective dosage and the shortest duration of therapy producing an adequate clinical response should be employed. The continued need for therapy should be assessed periodically. Because the risk of some of these effects may be increased in geriatric patients and because it is estimated that many geriatric patients residing in long-term care facilities are inappropriately prescribed antipsychotic therapy, it is important that the need for chronic therapy with the drugs be established in these patients. (See Geriatric Considerations under Psychotic Disorders: Schizophrenia and Other Psychotic Disorders, in Uses and see also Cautions: Geriatric Precautions.) Unless contraindicated, periodic efforts should be made in patients receiving long-term therapy to gradually reduce dosage and provide drug holidays and/or nondrug (e.g., behavioral) therapy in an attempt to discontinue antipsychotic drug therapy whenever clinically possible. Patients in whom long-term antipsychotic drug therapy is considered should be fully informed, if possible, about the risk of developing potentially irreversible adverse effects. Likewise, the decision to employ such therapy should be carefully considered by the patient (and/or the patient's family or guardians) and the physician if possible. The decision to inform the patient (and/or the patient's family or guardians) should take into account the clinical circumstances and the competency of the patient to understand the information.

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of mortality.330,335,336,337,338,342 (See Geriatric Considerations under Psychotic Disorders: Schizophrenia and Other Psychotic Disorders, in Uses and see also Cautions: Geriatric Precautions.)

Patients should be warned that phenothiazines may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Patients also should be warned that phenothiazines may enhance their response to alcohol, barbiturates, or other CNS depressants. Patients should also be warned to contact their physician if signs or symptoms of agranulocytosis such as sore throat or other signs of infection occur.

Phenothiazines and other antipsychotic agents may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur.410,411,412,413 For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.410,411,412,413

Because of the risk of adverse cardiovascular effects, phenothiazines should be used with caution in patients with severe cardiovascular disorders. Low-potency agents (such as thioridazine), in particular, should be avoided in patients with symptomatic orthostatic hypotension, and the drugs, particularly thioridazine and mesoridazine (no longer commercially available in the US), also should be avoided in those with established cardiac disease, particularly prolongation of the QT interval or a history of cardiac arrhythmias. Phenothiazine-treated patients who experience postural hypotension should be cautioned not to get up quickly and to obtain assistance when necessary. The management of mild to moderate cases of hypotension may include a variety of measures such as the use of support stockings, an increase in dietary salt intake, and/or fludrocortisone therapy. If severe hypotension occurs, norepinephrine, metaraminol, or phenylephrine may be used; epinephrine or dopamine, should not be used since phenothiazines cause a reversal of these drugs' vasopressor effects and a further lowering of blood pressure.

Because phenothiazines may lower the seizure threshold, the drugs should be used with caution in patients with a history of seizures and in those receiving anticonvulsant agents. Adequate anticonvulsant therapy should be maintained during administration of phenothiazines. If a patient receiving a phenothiazine or another antipsychotic agent (except clozapine) experiences a seizure, some authorities recommend the drug be withdrawn or the dosage reduced by 50% until a neurologic examination can be completed. In patients with a history of substance abuse or dependence, clinicians should consider the possibility that phenothiazines and other antipsychotic agents can infrequently precipitate seizures during alcohol or benzodiazepine withdrawal.

Patients receiving prolonged phenothiazine therapy with moderate to high dosages should have periodic ophthalmologic examinations. (See Cautions: Ocular Effects.)

Phenothiazines should be used with caution in debilitated patients, in patients with hepatic or renal disease, and in patients with glaucoma or prostatic hypertrophy. There is some evidence that patients with a history of hepatic encephalopathy secondary to cirrhosis have an increased sensitivity to CNS effects (i.e., impaired cerebration, slowing of the EEG) of phenothiazines. Phenothiazines should be administered with caution to patients exposed to organophosphate insecticides.

Because phenothiazines depress the hypothalamic mechanism for regulation of body temperature, the drugs should also be administered with caution to patients exposed to extreme heat or cold; patients receiving phenothiazines should be advised that they are likely to have increased vulnerability when exposed to temperature extremes, possibly resulting in hyperthermia or hypothermia. Because of the CNS depressant effects of phenothiazines, the drugs should be used with caution in patients with chronic respiratory disorders such as severe asthma, emphysema, or acute respiratory tract infections. Because phenothiazines may suppress the cough reflex, aspiration of gastric contents is possible.

Phenothiazines should be used with caution in patients with hypocalcemia because these patients appear to be more susceptible to dystonic reactions.

When concomitant therapy with an anticholinergic antiparkinsonian drug is necessary to manage phenothiazine-induced extrapyramidal symptoms, it may be necessary to continue the antiparkinsonian drug for a period of time after discontinuance of phenothiazines in order to prevent emergence of these symptoms. The combined anticholinergic effects of the drugs should be considered.

Because neurologic reactions resulting from phenothiazine therapy may be similar to CNS signs and symptoms accompanying certain disorders such as encephalitis, Reye's syndrome, encephalopathy, meningitis, and tetanus, the diagnosis of these disorders may be obscured or the disease-associated signs and symptoms may be incorrectly diagnosed as drug induced.

It should be kept in mind that the antiemetic effect of phenothiazines may mask the signs of overdosage of toxic drugs (e.g., antineoplastic agents) or may obscure the cause of vomiting in various disorders such as intestinal obstruction, Reye's syndrome, or brain tumor.

Phenothiazines should be administered with caution and in reduced dosage to patients who have exhibited severe reactions to insulin or electroconvulsive therapy (ECT).

In general, patients who have demonstrated a hypersensitivity reaction (e.g., cholestatic jaundice) to any phenothiazine derivative should not be reexposed to another derivative, unless the potential benefits of phenothiazine therapy outweigh the possible risks.

Some commercially available preparations (i.e., tablets) of phenothiazines contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.

Care should be taken to avoid skin contact with phenothiazine oral solutions and injections, since contact dermatitis has occurred rarely.

Phenothiazines are contraindicated in patients with severe toxic CNS depression or in those who are comatose from any cause. Phenothiazines also are contraindicated in patients with subcortical brain damage and in patients with bone marrow depression. Individual phenothiazines are contraindicated in patients who are hypersensitive to other phenothiazine derivatives unless the potential benefits outweigh the possible risks to the patient.

Because thioridazine and mesoridazine have been shown to prolong the QT interval corrected for rate (QT_c), which may be associated with life-threatening, proarrhythmic effects,312,313 concomitant use of these phenothiazines with drugs that prolong the QT_c interval is contraindicated.312,313 Use of these phenothiazines also is contraindicated in patients with underlying conditions (e.g., congenital long QT syndrome, history of arrhythmias) that might prolong the QT_c interval.312,313 In addition, thioridazine is contraindicated in patients receiving drugs that inhibit the cytochrome P-450 (CYP) 2D6 isoenzyme (e.g., fluoxetine, paroxetine) or reduce clearance of thioridazine by other mechanisms (e.g., fluvoxamine, pindolol, propranolol) and in those with poor metabolizer phenotypes of the CYP2D6 isoenzyme.306,307,312

Pediatric Precautions

Because children and adolescents may have substantial adverse effects that have yet to be identified, documentation of and monitoring for known adverse effects (e.g., extrapyramidal effects, weight gain) is required when phenothiazines are used in the management of childhood-onset schizophrenia.319 The risk of extrapyramidal adverse effects associated with antipsychotic agents, including phenothiazines, may be higher in children and adolescents than in adults.319 As many as 50% of children and adolescents who receive antipsychotic agents may experience some form of tardive or withdrawal dyskinesia.319 In addition, an analysis of published reports of neuroleptic malignant syndrome (NMS) in 77 children and adolescents who received antipsychotic agents showed that 9% of these patients died and another 20% had serious residual sequelae.319,324 Dopamine agonists (e.g., bromocriptine) and anticholinergic agents that are used to treat the syndrome in adults were effective in these children and adolescents, but dantrolene, a skeletal muscle relaxant, was not effective in these patients.319 However, these reports are not definitive and further studies are needed.319

Phenothiazines should be used with caution in children with acute illnesses (e.g., varicella-zoster [chickenpox] infections, CNS infections, measles, gastroenteritis) or dehydration, since the incidence of extrapyramidal symptoms, especially dystonic reactions and akathisia, is increased in these patients.

Phenothiazines should not be used in children in conditions for which pediatric dosage has not been established. For specific recommendations regarding use of these drugs in children, see the individual monographs on phenothiazines in 28:16.08.24.

Geriatric Precautions

Clinical studies of phenothiazines (e.g., perphenazine) generally did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.325 Although other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.325 The greater frequency of decreased hepatic function and of concomitant disease and drug therapy observed in the elderly also should be considered.325

Geriatric patients appear to be particularly sensitive to adverse nervous system (e.g., tardive dyskinesia, parkinsonian signs and symptoms, akathisia, sedation), anticholinergic, and cardiovascular (e.g., orthostatic hypotension) effects of antipsychotic agents.325 Because the risk of falling and associated hip fracture in geriatric patients may be increased with use of antipsychotic agents, phenothiazine therapy should be initiated at reduced dosages and such patients observed closely.325

Geriatric patients with dementia-related psychosis treated with either conventional (first-generation) or atypical (second-generation) antipsychotic agents are at an increased risk of mortality.330,335,336,337,338,342 Analyses of 17 placebo-controlled trials (average duration of 10 weeks) in geriatric patients mainly receiving atypical antipsychotic agents revealed an approximate 1.6- to 1.7-fold increase in mortality compared with that in patients receiving placebo.335,342 Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in those receiving placebo.330,335 Although the causes of death were varied in these trials, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.330,335 Subsequently, two observational, epidemiological studies have indicated that, similar to atypical antipsychotic agents, treatment of geriatric patients with conventional antipsychotic agents may increase mortality; the causes of death were not reported in the first study and cancer and cardiac disease were the causes of death with the highest relative risk in the second study.335,336,337,338 However, the extent to which these findings of increased mortality in observational studies may be attributed to the antipsychotic agent as opposed to certain patient characteristics remains unclear.337,338 The US Food and Drug Administration (FDA) currently advises clinicians that antipsychotic agents are not approved for the treatment of dementia-related psychosis.335,336 The FDA further advises clinicians that no drugs currently are approved for the treatment of patients with dementia-associated psychosis and that other management options should be considered in such patients.335,336 The decision whether to prescribe antipsychotic agents “off-label” in the treatment of dementia symptoms is left to the discretion of the clinician.336,342 Clinicians who prescribe antipsychotic agents in geriatric patients with dementia-related psychosis should discuss the increased mortality risk with patients, their families, and their caregivers.335 In addition, patients currently receiving antipsychotic agents for dementia-associated symptoms should not abruptly stop taking the drugs; caregivers and patients should discuss any possible concerns with their clinician.336 For additional information on the use of antipsychotic agents for dementia-associated psychosis and other behavioral disturbances, see Geriatric Considerations under Psychotic Disorders: Schizophrenia and Other Psychotic Disorders, in Uses.

Geriatric patients with genetic deficiency of the cytochrome P-450 (CYP) 2D6 isoenzyme (i.e., those with the poor-metabolizer phenotype) appear to be at increased risk for drug-induced adverse effects when receiving usual dosages of phenothiazines that are metabolized principally via this pathway.325 In one study in 45 geriatric patients with dementia, the 5 patients who were prospectively identified as exhibiting the poor-metabolizer phenotype reported greater adverse effects during the first 10 days of perphenazine therapy than did the 40 patients exhibiting the extensive-metabolizer phenotype; thereafter, the adverse-effect profiles for the 2 groups tended to converge.325 One manufacturer of perphenazine states that phenotyping of geriatric patients prior to initiation of antipsychotic therapy may identify those at risk for adverse events.325 Some authorities also recommend that a comprehensive medical, psychiatric, and psychosocial examination be performed before prescribing antipsychotic agents in elderly patients. In addition, a baseline leukocyte count is useful in older patients treated with antipsychotic agents for the first time since these drugs, particularly phenothiazines, can lower the leukocyte count. (See Cautions: Hematologic Effects.) If the baseline leukocyte count is low or if the patient is receiving another drug that also may lower the leukocyte count, then a nonphenothiazine antipsychotic agent may be preferable.

Mutagenicity and Carcinogenicity

Chromosomal aberrations in spermatocytes and abnormal sperm have been demonstrated in rodents treated with certain neuroleptic drugs.

Although an increase in mammary neoplasms has been found in rodents following long-term administration of prolactin-stimulating antipsychotic agents, no clinical or epidemiologic studies conducted to date have shown an association between long-term administration of these drugs and mammary tumorigenesis in humans. Current evidence is considered too limited to be conclusive, and further study is needed to determine the clinical importance in most patients of elevated serum prolactin concentrations associated with antipsychotic agents. Because in vitro tests indicate that approximately one-third of human breast cancers are prolactin dependent, phenothiazines should be used with caution in patients with previously detected breast cancer. Because clozapine causes only small, transient increases in prolactin concentrations (see Pharmacology: Neuroendocrine Effects, in Clozapine 28:16.08.04), it has been suggested that clozapine theoretically may be safer than other antipsychotic drugs for patients with schizophrenia who also are at high risk for or who have a history of breast cancer.

Pregnancy, Fertility, and Lactation

Pregnancy

Neonates exposed to antipsychotic agents, including phenothiazines, during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.357,358,359,360 On February 22, 2011, the US Food and Drug Administration (FDA) notified healthcare professionals that 69 cases of neonatal extrapyramidal symptoms or withdrawal have been identified with all antipsychotic agents in the Adverse Event Reporting System database through October 29, 2008.359 Symptoms reported in these cases included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder.357,358,359,360 Because antipsychotic plasma concentrations were not provided, the FDA states it was not possible to determine whether the events resulted from antipsychotic toxicity or withdrawal.359 The majority of cases were also confounded by other factors, including concomitant use of other drugs associated with withdrawal symptoms (e.g., antidepressant agents, benzodiazepines, nonbenzodiazepine hypnotics, opiate agonists), prematurity, congenital malformations, and obstetric and perinatal complications (e.g., placental problems, preeclampsia).359 However, there were some cases that suggested neonatal extrapyramidal symptoms and withdrawal may occur with exposure to antipsychotic agents alone.357,359 Some of the cases described time of symptom onset, which ranged from birth to one month after birth.357,358,359 Any neonate exhibiting extrapyramidal or withdrawal symptoms following in utero exposure to antipsychotic agents should be monitored.359 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive care unit support and prolonged hospitalization.357,358,359,360 Drugs that have been used to treat suspected withdrawal reactions include phenobarbital and benzodiazepines.359

Safety of phenothiazines during pregnancy has not been established. Animal reproduction studies have not been performed with most of the phenothiazines. It is not known whether phenothiazines can cause fetal harm when administered to pregnant women. Although several retrospective studies of infants born to women treated with a phenothiazine (e.g., chlorpromazine, trifluoperazine) have found no increased risk of adverse fetal effects associated with phenothiazine use, one study found an increased risk of malformations. In addition, prolonged jaundice, extrapyramidal symptoms, hyperreflexia, and hyporeflexia have occurred in some neonates born to women who were receiving phenothiazines during pregnancy.360 Phenothiazines should generally be used during pregnancy only when the potential benefits justify the possible risks to the fetus.359,360 Clinicians should advise women of childbearing potential about the benefits and risks of antipsychotic agent therapy during pregnancy.359 Patients should also be advised not to stop taking their antipsychotic agent if they become pregnant without first consulting with their clinician, since abruptly discontinuing the drugs can cause clinically important complications.359 In cases where antipsychotic agents must be used during pregnancy because the patient's psychosis places the mother and/or her fetus at substantial risk, some experts state that high-potency agents may be safer. In addition, the drug should be given in the lowest effective dosage and for as brief a period as possible and should be discontinued at least 5-10 days prior to anticipated delivery. Phenothiazines are generally contraindicated during the first trimester of pregnancy, particularly between weeks 6 and 10.

Fertility

The effect of phenothiazines on fertility in humans is not known. Impotence, increased or decreased libido, inhibition of ejaculation, amenorrhea, and menstrual irregularities have occurred in some individuals during phenothiazine therapy.

Lactation

Phenothiazines are distributed into milk. The manufacturers warn that nursing should not be undertaken by women receiving phenothiazines.

CNS Depressants

Phenothiazines may be additive with, or may potentiate the action of, other CNS depressants such as opiates or other analgesics, barbiturates or other sedatives, general anesthetics, or alcohol. When phenothiazines are used concomitantly with other CNS depressants, caution should be used to avoid excessive sedation or CNS depression.

Anticonvulsants

Because phenothiazines may lower the seizure threshold, dosage adjustment of anticonvulsant agents may be necessary when the drugs are used concomitantly. The CNS depressant effects of phenothiazines do not potentiate the anticonvulsant activity of anticonvulsants. Chlorpromazine reportedly has decreased the metabolism of phenytoin; if the drugs are used concomitantly, the patient should be closely monitored for phenytoin toxicity. Phenobarbital has been shown to increase urinary excretion and to decrease plasma concentrations of chlorpromazine. Although the clinical importance of this potential interaction has not been determined, the possibility that the therapeutic effects of chlorpromazine may be reduced during concurrent therapy with the drugs should be considered.

Lithium

Although most patients receiving lithium and a phenothiazine antipsychotic agent concurrently do not develop unusual adverse effects, an acute encephalopathic syndrome occasionally has occurred, especially when high serum lithium concentrations were present. Patients receiving such combined therapy should be observed for evidence of adverse neurologic effects; treatment should be promptly discontinued if such signs or symptoms appear. (See Drug Interactions: Antipsychotic Agents, in the monograph on Lithium Salts 28:28.)

Metrizamide

Animal studies suggest an increased risk of seizures when metrizamide (no longer commercially available in the US) is administered concurrently with drugs that lower the seizure threshold; however, the clinical importance of such an interaction has not been clearly established. The manufacturers have stated that phenothiazines should not be used in patients receiving metrizamide. Phenothiazines should be discontinued, if possible, at least 48 hours before and for at least 24-48 hours after administration of metrizamide. The manufacturers also stated that phenothiazines should not be used for the control of metrizamide-induced nausea and vomiting. However, if vomiting is severe, some clinicians believe that the benefit of a single dose of a phenothiazine may outweigh the low risk of seizures.

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of phenothiazines that are metabolized by the cytochrome P-450 (CYP) 2D6 isoenzyme (e.g., perphenazine, thioridazine) with drugs that inhibit the activity of CYP2D6 may increase plasma concentrations of the phenothiazine.312,325 (See Pharmacokinetics: Elimination.) Drugs that inhibit CYP2D6 activity include some of the tricyclic antidepressants and selective serotonin-reuptake inhibitors (e.g., fluoxetine, sertraline, paroxetine).312,325 Because thioridazine has been shown to prolong the QT interval corrected for rate (QT_c) in a dose-dependent manner, increased plasma concentrations of the drug may be expected to augment such prolongation and thus may increase the risk of serious, potentially fatal, cardiac arrhythmias (e.g., atypical ventricular tachycardia [torsades de pointes]).307,312,318 Therefore, concomitant use of thioridazine with drugs that inhibit the CYP2D6 isoenzyme is contraindicated.306,307,312 In patients receiving other phenothiazines (e.g., perphenazine), close monitoring is essential and dose reduction may be necessary to avoid toxicity if a drug that inhibits the activity of CYP2D6 is added to the existing drug regimen.325 In such patients, lower than usual dosages of either the phenothiazine or the other drug may be required.325

Other Drugs

The possibility that concomitant use of drugs that can reduce the clearance of thioridazine by other mechanisms (e.g., fluvoxamine, propranolol, pindolol) may result in accumulation of potentially cardiotoxic concentrations of this phenothiazine should be considered.312 The manufacturers of thioridazine state that concomitant use of thioridazine with such drugs is contraindicated.312 In addition, although specific drug interaction studies have not been performed to evaluate the concomitant use of thioridazine with drugs that prolong the QT_c interval, the manufacturers state that additive effects of such concomitant therapy on the QT_c interval can be expected and therefore such use is contraindicated.312 For additional information, see Drug Interactions in Thioridazine 28:16.08.24.

Laboratory Test Interferences

Urinary metabolites of phenothiazines may cause the urine to darken and result in false-positive test results for urobilinogen, amylase, uroporphyrins, porphobilinogens, and 5-hydroxyindolacetic acid. False-positive test results for phenylketonuria (PKU) may also occur during phenothiazine use.

False-positive pregnancy test (e.g., frog test, Gravindex^®, HCG test, Pregnosticon^®, UCG test) results have reportedly occurred in some patients receiving phenothiazines.

Acute Toxicity

Manifestations

In general, overdosage of phenothiazines may be expected to produce effects that are extensions of common adverse reactions; severe extrapyramidal reactions, hypotension, and sedation have been the principal effects reported. CNS depression progressing to coma with areflexia or CNS stimulation with convulsions followed by respiratory depression may occur; patients with early or mild intoxication may experience drowsiness, restlessness, disorientation, confusion, and excitement. Other reported effects associated with acute phenothiazine overdosage have included shock (e.g., ECG changes and cardiac arrhythmias), increased QT and PR intervals, non-specific ST and T wave changes, bradycardia, sinus tachycardia, bilateral bundle branch block, atrioventricular block, ventricular tachycardia, ventricular fibrillation, torsades de pointes, myocardial depression, agitation, dry skin, nasal congestion, urinary retention, oliguria, uremia, blurred vision, hypothermia, hyperthermia, mydriasis, miosis, tremor, muscle twitching, spasm or rigidity, seizures, muscular hypotonia, constipation, ileus, dry mouth, vomiting, difficulty in swallowing or breathing, cyanosis, and respiratory and/or vasomotor collapse, and pulmonary edema, possibly with sudden apnea.

Treatment

Treatment of phenothiazine overdosage generally involves symptomatic and supportive care. There is no specific antidote for phenothiazine intoxication; however, anticholinergic antiparkinsonian drugs may be useful in controlling extrapyramidal reactions associated with phenothiazine overdosage. Following acute ingestion of the drugs, the stomach should be emptied by gastric lavage and consideration also should be given to repeated doses of activated charcoal.312,313 If the patient is comatose, having seizures or a dystonic reaction, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Gastric lavage may be useful even several hours after the drug has been ingested, since GI motility may be greatly reduced following overdosage of phenothiazines. Induction of emesis should generally not be attempted, since a phenothiazine-induced dystonic reaction of the head or neck may result in aspiration of vomitus during emesis. Administration of a saline cathartic may be beneficial in enhancing evacuation of the drug from the GI tract.

Cardiovascular monitoring should begin immediately and should include continuous ECG monitoring to detect possible arrhythmias.313 Treatment may include correction of electrolyte abnormalities and acid-base balance, lidocaine, phenytoin, isoproterenol, ventricular pacing, and defibrillation.313 Antiarrhythmic agents that can prolong the QT interval (e.g., class IA [disopyramide, procainamide, quinidine] or III agents) should be avoided in treating overdosage-associated arrhythmias in which prolongation of QT_c is a manifestation.313,314 Appropriate therapy (IV fluids and a vasopressor) should be instituted if hypotension occurs; epinephrine, bretylium, or dopamine should not be used (see Cautions: Cardiovascular Effects). For the management of refractory hypotension, vasopressors such as phenylephrine, levarterenol, or metaraminol may be used.313,314 Appropriate therapy should be instituted if excessive sedation occurs; CNS stimulants that may cause seizures should be avoided. If seizures occur, treatment should not include barbiturates because these drugs may potentiate phenothiazine-induced respiratory depression.312 Hypothermia is common and sometimes difficult to control. In some patients with acute toxicity, exchange transfusions may be useful, but hemodialysis, forced diuresis, hemoperfusion, or manipulation of urine pH is of little value in enhancing elimination of phenothiazines.

Pharmacology

Phenothiazines are conventional (first-generation, prototypical) antipsychotic agents. The drugs also have been described as neuroleptic agents because of their ability to induce the neuroleptic syndrome (i.e., depressed initiative, decreased affect, disinterest in surroundings, suppression of complex behavior and spontaneous movements, decreased aggressiveness and impulsivity, decreased psychotic symptoms, extrapyramidal activity).

Phenothiazine, the structural prototype of the phenothiazines, has been used as a urinary tract antiseptic and as an anthelmintic; however, the toxicity of the drug in producing anemia, hepatitis, and skin reactions precludes its use in humans. Phenothiazine is still used as an anthelmintic in veterinary medicine and as an insecticide.

The development of phenothiazine derivatives as psychopharmacologic agents resulted from the observation that certain phenothiazine antihistaminic compounds produced sedation. In an attempt to enhance the sedative effects of these drugs, promethazine and chlorpromazine were synthesized.

Chlorpromazine is the pharmacologic prototype of the phenothiazines. The pharmacology of phenothiazines is complex, and because of their actions on the central and autonomic nervous systems, the drugs affect many different sites in the body. Although the actions of the various phenothiazines are generally similar, these drugs differ both quantitatively and qualitatively in the extent to which they produce specific pharmacologic effects.

Nervous System Effects

In the CNS, phenothiazines act principally at the subcortical levels of the reticular formation, limbic system, and hypothalamus. Phenothiazines generally do not produce substantial cortical depression; however, there is minimal information on the specific effects of phenothiazines at the cortical level. Phenothiazines also act in the basal ganglia, exhibiting extrapyramidal effects.

The precise mechanism(s) of action, including antipsychotic action, of phenothiazines has not been determined, but may be principally related to antidopaminergic effects of the drugs. There is evidence to indicate that phenothiazines antagonize dopamine-mediated neurotransmission at the synapses. There is also some evidence that phenothiazines may block postsynaptic dopamine receptor sites. However, it has not been determined whether the antipsychotic effect of the drugs is causally related to their antidopaminergic effects. Phenothiazines also have peripheral and/or central antagonistic activity against α-adrenergic, serotonergic, histaminic (H₁-receptors), and muscarinic receptors. Phenothiazines also have some adrenergic activity, since they block the reuptake of monoamines at the presynaptic neuronal membrane, which tends to enhance neurotransmission. The effects of phenothiazines on the autonomic nervous system are complex and unpredictable because the drugs exhibit varying degrees of α-adrenergic blocking, muscarinic blocking, and adrenergic activity. The antipsychotic activity of phenothiazines may be related to any or all of these effects, but it has been suggested that the drugs' effects on dopamine are probably most important. It has also been suggested that effects of phenothiazines on other amines (e.g., γ-aminobutyric acid [GABA]) or peptides (e.g., substance P, endorphins) may contribute to their antipsychotic effect. Further study is needed to determine the role of central neuronal receptor antagonism and of effects on biochemical mediators in the antipsychotic action of the phenothiazines and other antipsychotic agents.

Phenothiazines produce varying degrees of sedation without hypnosis or anesthesia in normal and psychotic patients; however, the drugs potentiate the CNS depressant actions of sedatives, hypnotics, and anesthetics. (See Drug Interactions: CNS Depressants.) Tolerance to the sedative effects develops over a period of days or weeks during long-term therapy. Phenothiazines increase total sleep time, tend to normalize sleep disturbances in psychotic patients, and decrease rapid eye movement (REM) sleep. Phenothiazines may cause EEG changes, including a slowing of the EEG pattern and an increase in theta - and delta -wave activity. Some decrease in fast-wave and alpha -wave activity also occurs. Phenothiazines also may lower the seizure threshold and induce discharge patterns associated with seizure disorders; overt seizures may occur in patients with a history of seizure disorders or an underlying condition that predisposes the patient to seizure development.

Although the exact mechanism(s) of action has not been conclusively determined, phenothiazines have an antiemetic effect. The antiemetic activity may be mediated via a direct effect of the drugs on the medullary chemoreceptor trigger zone (CTZ), apparently by blocking dopamine receptors in the CTZ. Phenothiazines inhibit the central and peripheral effects of apomorphine and ergot alkaloids. Phenothiazines generally do not inhibit emesis caused by the action of drugs at the nodose ganglion or by local action on the GI tract.

In animals, phenothiazines inhibit conditioned avoidance behaviors and produce catalepsy. The drugs antagonize the behavioral effects mediated by amphetamines and other CNS stimulants. Like many other centrally acting agents, phenothiazines exhibit analgesic activity and potentiate the actions of analgesics.

Phenothiazines have a poikilothermic effect, interfering with temperature regulation in the hypothalamus; depending on environmental conditions, hypothermia or hyperthermia may occur.

Therapeutic dosages of phenothiazines have little effect on respiration; however, phenothiazines enhance the respiratory depression produced by other CNS depressants. (See Drug Interactions: CNS Depressants.)

The peripheral anticholinergic activity of phenothiazines is relatively weak; however, anticholinergic effects (e.g., dry mouth, blurred vision, urinary retention, constipation) have been associated with their use in some patients. (See Cautions: Nervous System Effects.)

Cardiovascular Effects

The cardiovascular effects of phenothiazines are complex because the drugs exert both direct and indirect actions on the heart and vasculature. Phenothiazines exhibit peripheral α-adrenergic blocking activity and cause vasodilation. Following IV administration, the drugs cause orthostatic hypotension and reflex tachycardia; following oral administration, the drugs cause mild hypotension. (See Cautions: Precautions and Contraindications.) In addition, phenothiazines exert a negative inotropic effect at therapeutic dosages. The drugs may increase coronary blood flow as a result of an increase in heart rate.

Although phenothiazines do not appear to have clinically important antiarrhythmic properties at therapeutic dosages, transient antiarrhythmic effects have been observed in some patients at high concentrations. Antiarrhythmic effects may result from either a direct quinidine-like property or a local anesthetic effect of the drugs. Minimal ECG changes, including prolongation of the QT and PR intervals, blunting of T waves, and ST-segment depression, have occurred in some patients receiving phenothiazines. (See Cautions: Cardiovascular Effects.)

Endocrine Effects

Phenothiazines may affect the endocrine system. Phenothiazines induce secretion of prolactin from the anterior pituitary by inhibiting dopamine receptors in the pituitary and hypothalamus. Elevated prolactin concentrations generally persist during long-term administration and may be associated with galactorrhea, menstrual cycle changes (e.g., oligomenorrhea, amenorrhea), and gynecomastia. In contrast to the phenothiazines and other typical antipsychotic drugs, clozapine generally produces little or no elevation of prolactin concentration at usual dosages in humans. (See Pharmacology: Neuroendocrine Effects, in Clozapine 28:16.08.04.)

Phenothiazines may decrease urinary concentrations of gonadotropin, estrogen, and progestins in some patients. Although the exact mechanism is not known, phenothiazines may decrease secretion of vasopressin and corticotropin.

Other Effects

Phenothiazines may have anti-inflammatory and antipruritic effects, resulting from antagonism of various mediator substances (e.g., serotonin, histamine, bradykinin). At high concentrations, phenothiazines also have a membrane-stabilizing property, which can be manifested as a local anesthetic effect or as a direct quinidine-like effect on the heart.

Pharmacokinetics

Absorption

Phenothiazines are generally well absorbed from the GI tract and from parenteral sites; however, absorption may be erratic, particularly following oral administration. Considerable interindividual variations in peak plasma concentrations have been reported. The variability may result from genetic differences in the rate of metabolism, biodegradation of the drug in the GI lumen, and/or metabolism of the drug during absorption (in the GI mucosa) and first pass through the liver. Plasma concentrations of some phenothiazine derivatives (e.g., perphenazine, thioridazine) that are metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, particularly the CYP2D6 isoenzyme, may be elevated in patients with the poor-metabolizer phenotype.325 (See Pharmacokinetics: Elimination.) Such elevations may vary depending on the fraction of the drug that is metabolized by the CYP2D6 isoenzyme.312,325 Poor metabolizers may have an increased risk of adverse effects (e.g., cardiac toxicity) when receiving phenothiazines that are metabolized principally by CYP2D6.312 (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Although not clearly established for all derivatives, some phenothiazines (e.g., chlorpromazine) and their metabolites undergo enterohepatic circulation. (See Pharmacokinetics: Elimination.)

Therapeutic ranges for plasma drug concentrations of phenothiazines and the relationship of plasma concentrations to clinical response and toxicity have not been clearly established.

Distribution

Phenothiazines and their metabolites are distributed into most body tissues and fluids, with high concentrations being distributed into the brain, lungs, liver, kidneys, and spleen.

Phenothiazines are highly bound to plasma proteins.

Phenothiazines readily cross the placenta. It is not known if the drugs are distributed into milk; however, the size of the molecules and their ability to readily cross the blood-brain barrier suggest that the drugs would be distributed into milk.

Elimination

Although the exact metabolic fate of phenothiazines has not been clearly established, the drugs are extensively metabolized, principally in the liver via hydroxylation, oxidation, demethylation, sulfoxide formation, and conjugation with glucuronic acid; metabolic alterations in the side chain also may occur. Some phenothiazine derivatives (e.g., perphenazine, thioridazine) are metabolized by the cytochrome P-450 (CYP) 2D6 isoenzyme, which is under genetic control.325 The ability to metabolize phenothiazines via CYP2D6 is associated with the ability to oxidatively metabolize debrisoquin.325 Approximately 7-10% of Caucasians and a low percentage of Asians have little or no ability to oxidatively metabolize debrisoquin and exhibit the poor-metabolizer phenotype.312,325 The percentage of extensive- and poor-metabolizer phenotypes among other populations has not been precisely determined.325 Individuals who extensively metabolize drugs via the CYP2D6 pathway exhibit the extensive-metabolizer phenotype, while those who have an impaired ability to metabolize the drugs by this pathway exhibit the poor-metabolizer phenotype.325 Individuals with the poor-metabolizer phenotype will metabolize phenothiazine derivatives (e.g., perphenazine, thioridazine) that are metabolized by CYP2D6 more slowly and will experience higher concentrations at usual dosages compared with those exhibiting the extensive-metabolizer phenotype.325 Because increased plasma concentrations of thioridazine may be expected to augment QT interval prolongation and thus may increase the risk of serious, potentially fatal, cardiac arrhythmias (e.g., atypical ventricular tachycardia [torsades de pointes]), use of the drug is contraindicated in patients with the poor-metabolizer phenotype.312

Most metabolites of phenothiazines are pharmacologically inactive; however, certain metabolites (e.g., 7-hydroxychlorpromazine, mesoridazine) show moderate pharmacologic activity and may contribute to the action of the drugs. There is limited evidence to indicate that some phenothiazines (e.g., chlorpromazine) may induce their own metabolism.

Phenothiazines and their metabolites are excreted in urine and feces; the excretory patterns have not been fully characterized. The drugs are excreted in the feces via biliary elimination, principally as metabolites, and also appear to undergo enterohepatic circulation. Certain metabolites and unchanged drugs have been detected in urine in some patients for up to 6 months following discontinuance of therapy with a phenothiazine derivative.

Chemistry and Stability

Chemistry

Phenothiazines are conventional (prototypical, first-generation) antipsychotic agents. Phenothiazine is the structural prototype of the phenothiazines. Phenothiazine derivatives differ by substitution of various alkylamino groups on the nitrogen atom at the 10 position of the basic phenothiazine nucleus, and may be classified on the basis of the substituent as follows:

ETHYLAMINO DERIVATIVES

• ethopropazine
• promethazine
• propiomazine

PROPYLAMINO DERIVATIVES

• chlorpromazine
• methotrimeprazine
• promazine
• triflupromazine
• trimeprazine

PROPYLPIPERAZINE DERIVATIVES

• acetophenazine
• fluphenazine
• perphenazine
• prochlorperazine
• thiethylperazine
• trifluoperazine

ALKYLPIPERIDINE DERIVATIVES

• thioridazine

MISCELLANEOUS ALKYL NITROGEN DERIVATIVES

• methdilazine

The chemical group at the 10 position of the phenothiazine nucleus appears to determine the antipsychotic efficacy; compounds with 3 carbons between the 2 nitrogens have increased inhibitory effects on conditioned avoidance behaviors and enhanced α-adrenergic blocking activity, whereas compounds with 2 carbons between the nitrogens have predominantly antihistaminic activity. Substitution at the 2 position of the phenothiazine nucleus generally alters the potency and the incidence and/or severity of adverse effects associated with these drugs. The substituents at the 2 position of the phenothiazine nucleus have approximately the following order of relative potency: CF₃ > Cl > H approximately equal to OCH₃ approximately equal to CONHNH₂.

Phenothiazine derivatives are strong amines and have alkaline properties. These drugs usually are commercially available as salts of various acids and have a wide range of solubility in water and in alcohol.

Stability

Commercially available preparations of phenothiazine derivatives should be stored in tight, light-resistant containers at a temperature less than 40°C, preferably between 15-30°C, unless otherwise specified by the manufacturer; freezing of the oral solutions and injections should be avoided. Slight yellowish discoloration of the oral solutions or injections will not affect potency or efficacy, but they should not be used if markedly discolored or if a precipitate is present. Oral solutions of phenothiazine derivatives should be dispensed in amber glass bottles.

Phenothiazine derivative injections are physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Only references cited for selected revisions after 1984 are available electronically.

301. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry . 2004; 161(Suppl):1-56.

302. American Psychiatric Association. DSM-IV™: diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:394-403,417-23.

303. Trzepacz P, Breitbart W, Levenson J et al for the American Psychiatric Association Working Group on Delirium. Practice guideline for the treatment of patients with delirium. Am J Psychiatry . 1999; 156(Supp 5):1-20.

304. Breitbart W, Marotta R, Platt MM et al. A double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized AIDS patients. Am J Psychiatry . 1996; 153:231-7. [PubMed 8561204]

305. Menza MA, Murray GB, Holmes VF et al. Decreased extrapyramidal symptoms with intravenous haloperoidol. J Clin Psychiatry . 1987; 48:278-80. [PubMed 3597329]

306. Kennedy RS. Novartis issues important change in Mellaril (thioridazine HCL) labeling. From Medscape news web site. [Web]

307. Dear doctor or pharmacist letter regarding important labeling changes for all dosage forms of Mellaril^® (thioridazine HCl). East Hanover, NJ: Novartis; 2000 Jul 7.

308. Weller E, Rowan A, Weller R et al. Aggressive behavior associated with attention-deficit/hyperactive disorder, conduct disorder, and developmental disabilities. J Clin Psychiatr . 1999; 17:2-7.

309. Reilly JG, Ayis SA, Ferrier IN et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet . 2000; 355:1048-52. [PubMed 10744090]

310. Le Blaye I, Donatini B, Hall M et al. Acute overdosage with thioridazine: a review of the available clinical exposure. Vet Hum Toxicol . 1993; 35:147-50. [PubMed 8470359]

311. Buckley NA, Whyte IM, Dawson AH. Cardiotoxicity more common in thioridazine overdose than with other neuroleptics. J Toxicol Clin Toxicol . 1995; 33:199-204. [PubMed 7760442]

312. Novartis. Mellaril^® (thioridazine HCl) tablets and oral solution and Mellaril-S^® (thioridazine) tablets, oral solution, and oral suspension prescribing information. East Hanover, NJ; 2000 Jun.

313. Novartis. Serentil^® (mesoridazine besylate) tablets, injection, and oral solution prescribing information. East Hanover, NJ; 2000 Aug.

314. Dear doctor letter regarding the addition of a black box warning to Serentil^® (mesoridazine besylate) prescribing information. East Hanover, NJ: Novartis; 2000 Sep.

315. Niemann JT, Stapczynski JS, Rothstein RJ et al. Cardiac conduction and rhythm disturbances following suicidal ingestion of mesoridazine. Ann Emerg Med . 1981; 10:585-8. [PubMed 7316263]

316. Marrs-Simon PA, Zell-Kanter M, Kendzierski DL et al. Cardiotoxic manifestations of mesoridazine overdose. Ann Emerg Med. 1988 17:1074-8.

317. Vertrees JE, Siebel G. Rapid death resulting from mesoridazine overdose. Vet Hum Toxicol . 1987; 29:65-7. [PubMed 3824877]

318. Novartis, East Hanover, NJ: Personal communication.

319. McClellan J, Werry J, the Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry . 2001; 40(Suppl 7): 4-23S.

320. Spencer EK, Kafantaris V, Padron-Gayol MV et al. Haloperidol in schizophrenic children: early findings from a study in progress. Psychopharmacol Bull . 1992; 28:183-6. [PubMed 1513922]

321. Pool D, Bloom W, Mielke DH et al. Controlled evaluation of loxitane in seventy-five adolescent schizophrenic patients Curr Ther Res Clin Exp . 1976; 19:99-104. Abstract.

322. Realmuto GM, Erickson WD, Yellin AM et al. Clinical comparison of thiothixene and thioridazine in schizophrenic adolescents. Am J Psychiatry . 1984; 141:440-2. [PubMed 6367494]

323. Kumra S, Frazier JA, Jacobsen LK et al. Childhood-onset schizophrenia. Arch Gen Psychiatry . 1996; 53:1090-7. [PubMed 8956674]

324. Silva RR, Munoz DM, Alpert M et al. Neuroleptic malignant syndrome in children and adolescents. J Am Acad Child Adolesc Psychiatry . 1999; 38:187-94. [PubMed 9951218]

325. Schering Corporation. Trilafon^® (perphenazine) tablets and injection prescribing information. Kenilworth, NJ; 2001 Jul

326. American Psychiatric Association. Practice guideline for the treatment of patients with Alzheimer's disease and other dementias of late life. Am J Psychiatry . 1997; 154:1-39.

327. Janssen, Titusville, NJ: Personal communication.

328. Arnott W. Risperdal^® (risperidone) and cerebrovascular adverse events in placebo-controlled dementia trials. Janssen-Ortho; 2002 Oct 11. From the health products and food branch of Health Canada website. [Web]

329. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry . 1997; 154(Suppl 4):1-63.

330. Food and Drug Administration. Public health advisory: deaths with antipsychotics in elderly patients with behavioral disturbances. Rockville, MD; 2005 Apr 11. From the FDA website. [Web]

331. Lieberman JA, Stroup TS, McEvoy JP et al. for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005; 353:1209-23.

332. Freedman R. The choice of antipsychotic drugs for schizophrenia. N Engl J Med. 2005; 353:1286-8. Editorial.

333. American Psychiatric Association. APA says CATIE schizophrenia study argues for full range of treatment options. Sept 19, 2005. Press release.

334. National Institute of Mental Health. NIMH study to guide treatment choices for schizophrenia. Sept 19, 2005. Press release.

335. Food and Drug Administration. FDA Alert: Information for healthcare professionals: conventional antipsychotics. Rockville, MD; 2008 Jun 16. From the FDA website. [Web]

336. Food and Drug Administration. FDA News: FDA requests boxed warnings on older class of antipsychotic drugs. Rockville, MD; 2008 Jun 16. From the FDA website. [Web]

337. Schneeweiss S, Setoguchi S, Brookhart A et al. Risk of death associated with the use of conventional versus atypical antipsychotic drugs among elderly patients. CMAJ . 2007; 176:627-32. [PubMedCentral][PubMed 17325327]

338. Gill SS, Bronskill SE, Normand ST et al. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med . 2007; 146:775-86. [PubMed 17548409]

339. Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA . 2005; 294:1934-43. [PubMed 16234500]

340. Ballard C, Waite J, Birks J. Atypical antipsychotics for aggression and psychosis in Alzheimer's disease. Cochrane Database Syst Rev . 2006; 2:CD003476.

341. Sultzer DL, Davis SM, Tariot PN et al. Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial. Am J Psychiatry . 2008; 165:844-54. [PubMedCentral][PubMed 18519523]

342. Jeste DV, Blazer D, Casey D et al. ACNP White Paper: update on use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology . 2008; 33:957-70. [PubMed 17637610]

343. Beier MT. Pharmacotherapy for behavioral and psychological symptoms of dementia in the elderly. Am J Health Syst Pharm . 2007; 64(Suppl. 1):S9-17. [PubMed 17215476]

344. Schneider LS, Tariot PN, Dagerman KS et al. for the CATIE-AD Study Group. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. N Engl J Med . 2006; 355:1525-38. [PubMed 17035647]

345. Rosenheck RA, Leslie DL, Sindelar JL et al. Cost-benefit analysis of second-generation antipsychotics and placebo in a randomized trial of the treatment of psychosis and aggression in Alzheimer Disease. Arch Gen Psychiatry . 2007; 64:1259-68. [PubMed 17984395]

346. Pentel PR, Benowitz NL. Tricyclic antidepressant poisoning: management of arrhythmias. Med Toxicol . 1986; 1:101-21. [PubMed 3784839]

347. Crome P. Poisoning due to tricyclic antidepressant overdosage: clinical presentation and treatment. Med Toxicol . 1986; 1:261-85. [PubMed 3537621]

348. Gosselin RE, Smith RP, Hodge HC et al. Clinical toxicology of commercial products. 5th ed. Baltimore: The Williams and Wilkins Co; 1984:III-205-13.

349. Goldfrank LR, Lewin NA, Flomenbaum NE et al. Psychotropics: antidepressants: tricyclics, tetracyclics, monoamine oxidase inhibitors, and others. In: Goldfrank LR, Flomenbaum NE, Lewin NA et al, eds. Goldfrank's toxicologic emergencies. 3rd ed. Norwalk, CT: Appleton-Century-Crofts; 1986:351-9.

350. Braden NJ, Jackson JE, Walson PD. Tricyclic antidepressant overdose. Ped Clin North Am . 1986; 33:287-98.

352. Woolf AD, Erdman AR, Nelson LS et al. Tricyclic antidepressant poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol . 2007; 45:203-33.

353. Pentel P, Peterson CD, Nelson LS. Asystole complicating physostigmine treatment of tricyclic antidepressant overdose. Ann Emerg Med . 1980; 9:580-90. [PubMed 7436069]

354. Suchard JR, Nelson LS. Assessing physostigmine's contraindication in cyclic antidepressant ingestions. J Emerg Med . 2003; 25:185-91. [PubMed 12902007]

355. Newton RW, Nelson LS. Physostigmine salicylate in the treatment of tricyclic antidepressant overdosage. JAMA . 1975; 231:941-3. [PubMed 1173100]

356. Holinger PC, Klawans HL, Nelson LS. Reversal of tricyclic-overdosage-induced central anticholinergic syndrome by physostigmine. Am J Psychiatry . 1976; 133:1018-23. [PubMed 961921]

357. Sexson WR, Barak Y. Withdrawal emergent syndrome in an infant associated with maternal haloperidol therapy. J Perinatol . 1989; 9:170-2. [PubMed 2738729]

358. Coppola D, Russo LJ, Kwarta RF Jr. et al. Evaluating the postmarketing experience of risperidone use during pregnancy: pregnancy and neonatal outcomes. Drug Saf . 2007; 30:247-64. [PubMed 17343431]

359. US Food and Drug Administration. FDA drug safety communication: Antipsychotic drug labels updated on use during pregnancy and risk of abnormal muscle movements and withdrawal symptoms in newborns. Rockville, MD; 2010 Feb 22. From the FDA website. [Web]

360. Sandoz Inc. Trifluoperazine hydrochloride tablets prescribing information. Princeton, NJ; 2010 Sep.

376. Qureshi SU, Rubin E. Risperidone- and aripiprazole-induced leukopenia: a case report. Prim Care Companion J Clin Psychiatry . 2008; 10:482-3. [PubMedCentral][PubMed 19287562]

378. Gajwani P, Tesar GE. Olanzapine-induced neutropenia. Psychosomatics . 2000; 41:150-1. [PubMed 10749954]

400. Waln O, Jankovic J. An update on tardive dyskinesia: from phenomenology to treatment. Tremor Other Hyperkinet Mov (N Y) . 2013; 3

401. Rakesh G, Muzyk A, Szabo ST et al. Tardive dyskinesia: 21st century may bring new treatments to a forgotten disorder. Ann Clin Psychiatry . 2017; 29:108-119. [PubMed 28207919]

403. Margolese HC, Chouinard G, Kolivakis TT et al. Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia. Can J Psychiatry . 2005; 50:703-14. [PubMed 16363464]

404. Lerner PP, Miodownik C, Lerner V. Tardive dyskinesia (syndrome): Current concept and modern approaches to its management. Psychiatry Clin Neurosci . 2015; 69:321-34. [PubMed 25556809]

405. Neurocrine Biosciences, Inc. Ingrezza^® (valbenazine) capsules prescribing information. San Diego, CA; 2017 Apr.

406. Lundbeck Inc. Xenazine^® (tetrabenazine) tablets prescribing information. Deerfield, IL; 2015 Jun.

407. Teva Pharmaceuticals USA, Inc. Austedo^® (deutetrabenazine) tablets prescribing information. North Wales, PA; 2017 Aug. [Web]

408. Hauser RA, Factor SA, Marder SR et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry . 2017; 174:476-84. [PubMed 28320223]

409. Fernandez HH, Factor SA, Hauser RA et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology . 2017; [PubMedCentral]

410. Allergan USA, Inc. Saphris^® (asenapine maleate) sublingual tablets prescribing information. Irvine, CA; 2017 Feb.

411. Mylan Pharmaceuticals Inc. Perphenazine film-coated tablets prescribing information. Morgantown, WV; 2018 Oct.

412. Sandoz Inc. Chlorpromazine hydrochloride sugar-coated tablets prescribing information. Princeton, NJ; 2017 Aug.

413. Lilly USA, LLC. Zyprexa^® (olanzapine) tablets and Zyprexa^® Zydis^® (olanzapine) orally disintegrating tablets and Zyprexa^® IntraMuscular (olanzapine) for injection prescribing information. Indianapolis, IN; 2018 Jan 23.

507. van de Loosdrecht AA, Faber HJ, Hordijk P et al. Clozapine-induced agranulocytosis: a case report. Immunopathophysiological considerations. Neth J Med . 1998; 52:26-9. [PubMed 9573739]

508. Sperner-Unterweger B, Czeipek I, Gaggl S et al. Treatment of severe clozapine-induced neutropenia with granulocyte colony-stimulating factor (G-CSF): remission despite continuous treatment with clozapine. Br J Psychiatry . 1998; 172:82-4. [PubMed 9534838]

509. Rudolf J, Grond M, Neveling M et al. Clozapine-induced agranulocytosis and thrombopenia in a patient with dopaminergic psychosis. J Neural Transm . 1997; 104:1305-11. [PubMed 9503276]

510. Wickramanayake PD, Scheid C, Josting A et al. Use of granulocyte colony-stimulating factor (filgrastim) in the treatment of non-cytotoxic drug-induced agranulocytosis. Eur J Med Res . 1995; 18:153-6.

511. Chin-Yee I, Bezchlibnyk-Butler K, Wong L. Use of cytokines in clozapine-induced agranulocytosis. Can J Psychiatry . 1996; 41:280-4. [PubMed 8793147]

512. Chengappa KN, Gopalani A, Haught MK et al. The treatment of clozapine-associated agranulocytosis with granulocyte colony-stimulating factor (G-CSF). Psychopharmacol Bull . 1996; 32:111-21. [PubMed 8927660]

513. van Melick EJ, Touw DJ, Haak HL. [Agranulocytosis caused by clozapine: the importance of leukocyte monitoring and efficacy of hematopoietic growth factors.] (Dutch; with English abstract.) Ned Tijdschr Geneeskd . 1995; 139:2437-40.

514. Gerson SL. G-CSF and the management of clozapine-induced agranulocytosis. J Clin Psychiatry . 1994; 55(Suppl B):139-42. [PubMed 7525542]

515. Gullion G, Yeh HS. Treatment of clozapine-induced agranulocytosis with recombinant granulocyte colony-stimulating factor. J Clin Psychiatry . 1994; 55:401-5. [PubMed 7523362]

516. Nielsen H. Recombinant human granulocyte colony-stimulating factor (rhG-CSF; filgrastim) treatment of clozapine-induced agranulocytosis. J Intern Med . 1993; 234:529-31. [PubMed 7693847]

517. Barnas C, Zwierzina H, Hummer M et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment of clozapine-induced agranulocytosis: a case report. J Clin Psychiatry. 1992; 53:245-7. [PubMed 1639744]

518. Means RT, Sandidge DR, Rankin KM et al. Treatment of phenothiazine-induced agranulocytosis with recombinant granulocyte colony-stimulating factor. Am J Hematol . 1992; 41:296. [PubMed 1283811]

519. Kendra JR, Rugman FP, Flaherty TA et al. First use of G-CSF in chlorpromazine-induced agranulocytosis: a report of two cases. Postgrad Med J . 1993; 69:885-8. [PubMed 7507240]