The newer antidepressants (SSRIs and SNRIs) are gradually replacing the older agents like tricyclics and MAOIs as the treatment of choice for various symptoms of depressive and anxiety disorders (Box 21-2 Target Symptoms of Depression and Box 21-3 Antidepressants). This change occurred because the newer agents have better side effect profiles. Owing to the broader mechanism of action of SNRIs on more than one neurotransmitter (e.g., norepinephrine and dopamine) they can be effective when SSRIs are not.
Hypotheses on Mechanisms of Action
The exact mechanisms of action of antidepressants are unknown, but the following are hypotheses concerning the various types of antidepressants.
Tricyclic Antidepressants TCAs may work by affecting serotonin, norepinephrine, and dopamine neurotransmitter systems. Their major side effects may be caused by interacting with muscarinic cholinergic receptors.
Monoamine Oxidase Inhibitors MAOIs potentiate neurotransmitters by inhibiting the function of the enzyme monoamine oxidase (MAO), which inactivates neurotransmitters. Inhibition of MAO, which is present in the central nervous system, gut, and platelets, may lead to increased absorption of tyramine, which can act as a false neurotransmitter and elevate blood pressure. Therefore, a tyramine-free diet is required with the use of MAOIs.
Selective Serotonin Reuptake Inhibitors SSRIs enhance serotonergic transmission, increasing serotonin in the synaptic clefts between neurons. This is caused by accumulation of serotonin in the cleft as the drug blocks the reuptake of serotonin back into the neuron.
Newer Agents (Non-SSRIs) Bupropion (Wellbutrin) is thought to work by inhibiting norepinephrine reuptake in addition to its effect on dopaminergic transmission. Venlafaxine (Effexor) and Duloxetine (Cynbalta) are selective inhibitors of serotonin and norepinephrine reuptake. Nefazodone (Serzone), which can be associated with liver failure, is thought to work by antagonizing serotonergic and alpha-1 adrenergic receptors.
All antidepressants have equal efficacy on symptoms of depressive episodes. Improvement of mood may not be observed for 2 to 6 weeks. Selection of agents is based on the agents' different side effect profiles and the patient's tolerance to them. There is no reliable method to predict which patients will respond better to a specific agent. The factors to consider for agent selection include the patient's age, suicide potential, concurrent use of medications, and coexisting diseases. For example, SSRIs are safer in patients with a history of cardiac diseases or suicidal ideations. If the patient or a first-degree relative has had a good response to a certain agent in the past, another trial of the same agent is an option because the agent may be compatible with the individual's metabolic capacity.
Common Side Effects of Antidepressants
Tricyclic Antidepressants and Monoamine Oxidase Inhibitors The major side effects of TCAs and MAOIs are lethargy, orthostatic hypotension, and anticholinergic symptoms (Table 21-3 Comparing Side Effects of SSRIs and TCAs/MAOIs). These side effects tend to increase during the first month of treatment but usually subside with time. The anticholinergic side effects include dry mucosa (mouth, nose, or vagina), blurred vision, urinary retention, poor memory, and impaired concentration. These can be caused by TCAs, MAOIs; low-potency antipsychotics such as thioridazine (Mellaril) and chlorpromazine (Thorazine), clozapine (Clozaril) (except dry mouth). These disturbing side effects must be managed to enhance compliance with the treatment (Table 21-4 Managing Anticholinergic and Other Common Side Effects of Antidepressants).
Selective Serotonin Reuptake Inhibitors and Non-SSRIs The common side effects of SSRIs include insomnia, sexual dysfunction, and agitation or restlessness. These are mediated by their interactions with the serotonin neu rotransmission system. The newer non-SSRI agents (bupropion, nefazodone, and mirtazapine) are associated with lower risks of sexual dysfunction. In akathisia-like restlessness, the dose may need to be reduced. Switching to another agent may be needed if the symptom is severe and persistent.
SSRI Withdrawal Syndrome Abrupt discontinuation of paroxetine or fluvoxamine can result in dizziness, nausea, irritability, headaches, or cholinergic rebound symptoms (e.g., salivation, loose stools).
Serotonin syndromeMental status changes, agitation, myoclonus, and hyperreflexia may result from the concomitant use of two or more drugs that may increase CNS serotonin level through different mechanisms. This can occur when SSRIs are taken along with other drugs that increase serotonin levels including sumatriptan, L-tryptophan, and TCAs.
Other Side Effects of Specific Antidepressants
AgranulocytosisMirtazapine (Remeron) can cause agranulocytosis or neutropenia in 1 in 1000 patients. It should not be used with bone marrow–suppressing agents such as carbamazepine (Tegretol), phenytoin (Dilantin), or clozapine (Clozaril)
Priapism The incidence of priapism with trazodone (Desyrel) is rare. If the erection persists longer than 1 hour, emergency room treatment is required. If not treated promptly, priapism may result in permanent impotence.
HypertensionVenlafaxine (Effexor) is associated with higher risks of hypertension.
SeizureBupropion (Wellbutrin) and clomipramine (Anafranil) have been associated with higher risks.
Liver DamageDuloxetine (Cymbalta) is not generally recommended with preexisting liver disease or alcohol abuse.
In 2004, the Food and Drug Administration (FDA) added a black box warning to antidepressants for children and adolescents with major depressive disorder of a potential increased risk for suicide. This action has contributed to a reduction in prescribing these medications (Schatzberg, Cole, & DeBattista, 2005; Leckman & King, 2007). This action may also have contributed to more untreated depression and possible increased suicide risk (American Psychiatric Association, 2006). More studies need to be done about the potential risks and benefits of antidepressants in this age group. In 2006 the FDA increased the age range on this warning to age 24. SSRIs are the most frequent type of antidepressants used in children due to side effect profile, although TCAs have been used for enuresis and attention deficit-hyperactivity disorder.
TCAs and SSRIs have shown no statistically significant evidence of increased risks for congenital defects or teratogenicity except for paroxetine (Paxil), which is associated with increased risk of cardiac birth defects when exposed in the first trimester. MAOIs are associated with higher risks. Discontinuing antidepressants in pregnancy can be associated with relapse of depression. So close monitoring must be maintained.
TCAs are of particular concern because of their anticholinergic side effects in this age group. Anticholinergics are a major contributor to delirium in the elderly (Schatzberg, Cole, & DeBattista, 2005). Urinary retention is a concern for men with enlarged prostates. Orthostatic hypotension can contribute to falls.
Other Clinical Concerns
QRS ProlongationA 1-week supply of TCAs may be fatal if taken all at once to reach two to six times therapeutic levels in blood (i.e., 500–1000 ng/mL).
Depressive Episodes Caused by Medical ConditionsPsychiatric symptoms of depression can be part of the clinical presentation of non-psychiatric illnesses such as Addison's disease, AIDS, asthma, heart failure, Cushing's disease, diabetes, hyperthyroidism and hypothyroidism, infectious hepatitis, and malnutrition. Psychiatric medications may be tried to manage the symptoms while the underlying medical conditions are being treated.
Mania All antidepressants can cause mania in patients with bipolar disorder.
Monoamine Oxidase Inhibitors and Food InteractionsMAOIs can cause high blood pressure, nausea, vomiting, and headaches as reactions with foods containing tyramine (Table 21-5 Foods to Avoid When Using MAOIs). All perishable foods (vegetables, fruits, and meats) should be as fresh as possible. The special diet needs to be continued for 4 weeks after the medicine is discontinued.
Use of St. John's Wort (Hypericum) St. John's Wort is an herbal product used for treatment of depression. Its mechanism is unclear. Randomized controlled trials have not supported its efficacy, but anecdotal reports have shown that it is helpful for some patients. It is contraindicated in pregnancy, lactation, and cardiovascular disease. Because of its possible MAOI-like activity, caution is required regarding its adverse reactions with serotonergic or sympathomimetic agents and foods containing tyramine.