A. Serotonin Specific Reuptake Inhibitors (SSRI) [1,2,4]

1. SSRI or SNRI are usually first line therapy for major depression
   1. Excellent side effect profile and reasonable efficacy
   2. Similar efficacy and safety of most classes of second-generation antidepressants [3,9]
   3. Combination of SSRI + benzodiazepine (for 14-21 days only) more effective than antidepressants alone [5]
   4. In children or young adults <18 years, only fluoxetine shows consistently safe results [47,49]
   5. In adolescents, fluoxetine superior to placebo, and fluoxetine + behavioral therapy superior to fluoxetine or behavioral therapy alone [49]
   6. Some increase in suicide risk within first 9 days of initiating a variety of antidepressants [48]
   7. Overall, SSRI and related antidepressants provide greater benefits than risks to adolescents with MDD, obsessive-compulsive disorder, anxiety [17]
2. Overview [4]
   1. Sertraline is usual choice in complex or older medical patient
   2. Flouxetine is often used younger medical patient
   3. Sertraline and fluoxetine approved for use in children
   4. Paroxetine is useful in less complex patients particularly with sleep problems
   5. Fluoxetine and paroxetine have significant CYP inhibition; drug interactions concerning
   6. Escitalopram and cialopram have very low potential for drug interactions
   7. For suboptimal or no response to initial SSRI, switching to another SSRI associated with ~50% good response rates [41]
   8. If no response to 2 SSRIs, switch to SNRI, other atypical, or TCA [41]
   9. Questions about paroxetine, citalopram, sertraline safety in children have arisen [44,45,47]
   10. Paroxetine and fluoxetine once daily are available as generics
   11. Generally safe in cardiovascular disease [58]
3. Sertraline (Zoloft®)
   1. Few side effects, few drug interactions, and short half life
   2. Agent of choice in older or complex patients and in children
   3. Initial dose is 50mg po qam up to 100mg po qam + 50mg po qpm (max 200mg per day)
   4. Maintenance for 18 weeks after initial 12 weeks is beneficial and well tolerated [24]
   5. Effective as second line therapy in patients with suboptimal citalopram responses [29]
   6. Safe and effective for major depression after acute coronary syndromes [6]
   7. Effective for dysthymia, better tolerated than imipramine
   8. Also approved for obsessive-compulsive disorder (OCD) and panic disorder
   9. Published studies show safe and effective for <18 year olds with major depression [45]
   10. Analysis of all studies suggest potential increase in suicide in persons <18 years old [47]
4. Flouxetine (Prozac®, Prozac® Weely and generic) [7]
   1. Preferred in less complex or younger medical patient; also approved in children
   2. Initial dose 20mg po qd (maximum 80 mg/d)
   3. Well tested, minimal drug interactions (compared with TCAs)
   4. In adolescents, fluoxetine superior to placebo, and fluoxetine + behavioral therapy superior to fluoxetine or behavioral therapy alone [49]
   5. Fluoxetine and paroxetine both metabolized through liver P450 system
   6. Elimination half-life 4-6 days; active metabolite norfluoxetine half-life 4-16 days
   7. Once weekly 90mg fluoxetine (Prozac® Weekly) can replace 20mg daily dose
   8. Recommend waiting 7 days after last 20mg dose before beginning Prozac® Weekly [7]
   9. Fluoxetine approved as Sarafem® (10mg, 20mg capsules) for premenstrual dysphoric disorder [8]
   10. Approved for treating depression in children [44] and safe in large meta-analysis [47]
5. Paroxetine (Paxil®)
   1. Comparable efficacy to fluoxetine
   2. Half-life is much shorter, and may have fewer long term effects
   3. More anti-cholinergic than fluoxetine and therefore more sedating
   4. Lower starting dose of 10 mg likely to be effective for elderly patients
   5. Typical dose is 10 to 20mg qd, up to 40-60mg/d for anxiety disorders
   6. Effective for dysthymia and minor depression in older adults (start at 10mg/d) [10]
   7. Useful for anxiety disorders including social phobia
   8. Particularly useful for patients with poor sleep; drug should be taken at night
   9. Reduces risk of severe depression accompanying high dose interferon alpha treatment [12]
   10. Superior to cognitive behavior or psychotherapy for maintenance in elderly persons [11]
   11. Should not be used in children where adverse effects 2X placebo rates [44,47]
6. Citalopram (Celexa®) [13]
   1. SSRI for depression treatment
   2. Initial dose 20mg per day; may increase to 40mg qd
   3. May have less cytochrome P450 inhibition than the other SSRI's
   4. With suboptimal responses, may add buproprion XR or buspirone with improved response and remission rates [29.30]
   5. Citalopram significantly more effective than placebo or psychotherapy in patients with depression post-CABG [59]
   6. Large overdoses can cause QT prolongation and convulsions (similar to other agents)
   7. Questionable safety in persons <18 years old [47]
   8. Now available in generic form
7. Escitalopram (Lexapro®) [14]
   1. S-entantiomer of citalopram
   2. Effective but with no clinical benefits over citalopram [43]
   3. After stroke, treatment with escitalopram 10-20mg qd was more effective than problem-solving therapy and placebo in preventing post-stroke depression [61]
   4. Dose 10-20mg po qd
   5. Side effects similar to other agents
8. Fluvoxamine (Luvox®) [15]
   1. Approved for depression and obsessive compulsive disorder
   2. Dose is 100-300mg per day
   3. Similar to other agents
9. Major Side Effects
   1. Generally well tolerated in adults (>18 years old)
   2. Nausea, abdominal cramping have been reported
   3. May reduce appatite and cause weight loss
   4. SSRIs have high rates of sexual dysfunction
   5. Serotonin discontinuation syndrome common, except for fluoxetine (see below)
   6. Most SSRIs inhibit various CYP 450 drug metabolizing enzymes [16]
   7. Therefore, drug combinations should be evaluated carefully
   8. Trying another drug in same class may be better
   9. Caution if maternal weight gain is low in pregnancy
   10. Only fluoxetine has a clear safety profile in a large meta-analysis in <18 year olds [47] and was clearly safe in a prospective study in adolescents [49]
   11. SSRIs appear to be less effective than TCA or SNRI with physical symptoms or pain present
10. Serotonin Discontinuation (Withdrawal) Syndrome [3]
    1. Due to abrupt cessation of drugs which increase serotonin levels
    2. May last days or longer
    3. Physical symptoms: imbalance, gastrointestinal symptoms, mailaise, fatigue
    4. Sensory and sleep disturbances
    5. Psychological symptoms: anxiety, agitation, crying spells, irritability
    6. Also prominent with venlafaxine (Effexor®)
11. SSRI's associated with increased risk of persistent pulmonary hypertension of newborn [54]
    1. Exposure of fetus after 20th week gestation associated with 6X increased risk
    2. SSRI use before the 20th week or use of other antidepressants had no increase in risk
12. SSRI's that cause withdrawal syndrome may do so on fetus in pregnant women [56,57]
    1. Exposure in utero in 3rd trimester can cause a neonatal serotonin syndrome
    2. Neonatal 5HT syndrome includes CNS signs, motor, respiratory, gastrointestinal signs that are usually gone by age of 2 weeks
13. Paroxetine (Paxil®) associated with neonatal convulsions; less so with other SSRIs [56]
14. Cautiously manage use of SSRI's in pregnant women

B. Mixed Reuptake Inhibitors (SNRI)

1. Venlafaxine (Effexor®) [18,19,46]
   1. Mixed serotonin and norepinephrine (NE) reuptake inhibitor (weak on dopamine receptors)
   2. Minimal anti-cholinergic, anti-histaminergic and anti-adrenergic effects
   3. Dose: start 37.5mg po bid, maximum 225-375mg/day
   4. Extended release (XR) form is now available for once daily dosing
   5. Venlafaxine XR has shown good efficacy in generalized anxiety disorder (GAD) as well as depression [20]
   6. May be effective in patients who respond poorly to other SSRIs
   7. Reasonable first line agent for treatment of depression with efficacy similar to SSRIs [46]
   8. Increased nausea, insomnia, sweating, nervousness compared with SSRIs
   9. Mild diastolic blood pressure elevations; significant discontinuation syndrome
   10. Slow down-titration required for patients discontuing venlafaxine
2. Desvenlafaxine (Pristiq®) [60]
   1. Main active metabolite of venlafaxine
   2. No clear advantage over venlafaxine
   3. Nausea, hypertension, sweating, insomnia, dry mouth, anorexia, dizziness occur
   4. Inhibits CYP2D6 and is metabolized by CYP3A4
   5. Dose is 50mg po qd; may increase to 100mg po qd
3. Duloxetine (Cymbalta®) [50,53]
   1. Mixed serotonin and norepinephrine (NE) reuptake inhibitor
   2. Minimal activities on other receptors
   3. Dose 30-40mg bid or 60mg qd
   4. Similar side effects as venlafaxine
   5. Approved in depression and diabetic neuropathic pain
   6. As or slightly more effective than fluoxetine or paroxetine
   7. Side effects: Nausea, dizziness, somnolence, constipation, asthenia, erectile dysfunction
   8. Abrupt withdrawal leads to irritability, headache, vomiting, insomnia
4. Nefazodone (Serzone®) [21]
   1. Relatively weak inhibition of serotonin and NE reuptake
   2. Blockade of serotonin 5-HT2A receptor is probably responsible for efficacy
   3. Blockade of 5HT2A receptor leads to increased serotonin signaling through 5HT-1
   4. Weak alpha1-adrenergic receptor antagonism
   5. About 50% of patients with depression respond to single agent nefazodone [22]
   6. When combined with psychotherapy >75% of patients respond [22]
   7. Dose 50-100mg po bid initially, up to 300mg po bid
   8. Better tolerated than imipramine and probably as effective as fluoxetine
   9. Side effects include headache, insomnia, relatively mild orthostasis, nausea
   10. Improves symptoms of anxiety and restores sleep patterns
   11. Less sexual dysfunction and sleep disturbances than SSRIs
   12. Useful in pospartum depression, severe depression, depression with anxiety [3]
   13. Inhibits cytochrome P450-3A4; increases benzodiazepine, MAO-inhibitor levels
   14. Do not use with agents that can prolong QT interval
5. Mirtazapine (Remeron®) [23,24]
   1. Tetracyclic antidepressant, unrelated to other agents
   2. Blockade of presynaptic a2-adrenergic receptors
   3. Leads to increases in NE and serotonin release in the brain
   4. Also blocks 5-HT2 and 5-HT3 receptors, so serotonin signalling primarily via 5-HT1
   5. Efficacy similar to SSRI's and TCAs; superior to trazodone
   6. Dose is 15mg/day initially, increased to 45mg/day slowly
   7. Doses below 15mg/day should be avoided except in liver or renal failure
   8. Transient somnolence (mainly low doses) is major side effect (>50%)
   9. Increased appetite (17%) and weight gain occurs in 12% of patients
   10. Should not be used MAO-inhibitors
6. Reboxetine (Edronax®, Vestral®)
   1. Selective NE reuptake inhibitor (SNRI) not yet approved in USA
   2. No effect on serotonin, dopamine or monoamine oxidase
   3. May be effective for patients with very severe depression
   4. As or more effective as fluoxetine, imipramine and desipramine
   5. Dose is 4mg po bid (2mg po bid for elderly) to a maximum dose of 12mg per day
   6. Dose should be reduced by 50% in liver or renal failure
   7. Viloxazine (Vivalan®), another NE reuptake inhibitor, is also being developed
7. Most of these agents show little effect on P450 enzymes, unlike SSRIs
8. Sexual dysfunction occurs and may be improved with sildenafil [36]

C. Tricyclic Antidepressants

1. Effective in 50-70% of patients
   1. Behavioral and physiological symptoms resolve first (usually 1-2 weeks)
   2. Cognitive symptoms exhibit delayed improvement (2-3 weeks)
   3. Levels of agent can be monitored in blood, usually only for nortriptyline
   4. Low dose TCA may be as effective as standard dose and are likely safer [40]
   5. Overdoses of TCA are very serious and easily fatal
   6. Efficacy similar to SSRI, with increased side effects
2. Classification (see below)
   1. Tertiary Amines: imipramine, amitriptyline
   2. Secondary Amines: nortriptyline, desipramine
3. Pharmacology
   1. Tertiary amines shown above are demethylated by liver to 2° amines
   2. Secondary amines have longer t1/2 than 3° amines
   3. Half lives generally >18 hours in adults
4. Metabolic Conversions
   1. Amitriptyline to Nortriptyline
   2. Imipramine to Desipramine
   3. Doxepin to Desmethyldoxepin
5. Mechanisms of Action
   1. Defects in depression are not well known
   2. TCAs inhibit of re-uptake (inactivation) of neurotransmitters
   3. Specifically, block reuptake of norepinephrine +/- serotonin (limbic transmitters)
   4. Little effect on dopamine re-uptake
6. Additional Therapeutic Activities
   1. Anxiolytic, treatment of Panic Attacks
   2. Migraine Prophylaxis
   3. Chronic Pain treatment
   4. Treatment of sleep disorders
7. Additional Physiological Activities
   1. Anti-cholinergic: dry mouth, arrhythmia; much increased with tertiary (3°) amines
   2. Anti alpha-adrenergic: orthostatic hypotension; increased with 3° amines
   3. Anti-H1-histaminic: sedating; increased with 3° amines
8. Side Effects
   1. Anti-cholinergic: Sedation, dry mouth, urinary retention, dry eyes
   2. Possible potentiation of glaucoma
   3. Orthostatic hypotension (little vagolytic activity, however)
   4. May precipitate arrhythmias in patients with preexisting conditions
   5. Prolonged QRS interval may lead to ventricular fibrillation (Cardiac Arrest)
   6. Induce QTc prolongation which may progress to Torsade des pointes [26]
   7. TCA use has also been associated with 2.2 fold increased risk of heart attack [27]
   8. Confusional state, decreased alertness (due to antihistamine action)
   9. These agents appear to be safe in pregnancy but concerns on cardiac anomalies
9. Drug Interactions
   1. Prolong half-life of neuroleptics
   2. Potentiate action of sympathomimetics
   3. Additivity with other anti-cholinergics
10. Standard Doses for Treatment of Depression
    1. Amitriptyline (Elavil®, Endep®) - 150mg qd, 300mg max qd (3° Amine)
    2. Nortriptyline (Pamelor®, Aventyl®) - 100mg qd, 150mg max qd (2° Amine)
    3. Desipramine (Norpramin®, Pertofrane®) - 75-100mg po qd, 300mg max qd (2° Amine)
    4. Imipramine (Tofranil®, Janimine®, others) - 150mg po qd, 200mg max qd (3° Amine)
    5. Doxepin (Adapin®, Sinequan®) - 100-150mg po qd, 300mg max qd
    6. Lower doses of TCAs (75-100mg/d maximum) may be as effective as standard [40]f
11. Dosing Considerations
    1. Caution in setting of arrhythmias and QTc prolongation
    2. Generally start at low doses, 10-25mg po qhs
    3. Doxepin is available as liquid (10mg/mL) and can be started at very low doses
    4. Anti-depressant effects require 2-4 weeks for action
    5. Usual therapeutic level is 50-100 ng/mL, but monitoring levels is less common now
12. Combination nortriptyline and psychotherapy is more effective than either alone [28]

D. Other Agents

1. Use if side effects of above agents are not tolerated, or they are not effective
2. Bupropion XR (Welbutrin® XL, Budeprion XL) [3]
   1. Inhibits both norepinephrine and dopamine reuptake without serotonin effects
   2. May be stimulating and cause insomnia (tremors, rarely seizures)
   3. As effective as TCA, SSRI, and can be used as adjunctive therapy [29,30]
   4. Least amount of sexual dysfunction of all agents
   5. Significant reduction in smoking cessation (may be combined with nicotine)
   6. Generally safe in cardiovascular disease [58]
   7. Does not cause weight gain or sedation; may be slightly activating for patients
   8. Starting dose: 150mg qd, maximum 300mg qd
3. Trazodone (Desyrel®)
   1. Mainly for sleep disorders with good activity for insomnia
   2. Weak activity on serotonin transport, 5-HT2A receptors
   3. Activity at 5HT1A receptors may increase anxiolytic activity
   4. Mild anti-depressant effects, weaker than other agents
   5. May be added to SSRIs and other agents if insomnia is a problem
   6. Agent may be useful in patients with manic response to SSRIs (as second agent)
   7. Cerebral alpha1-adrenergic and H1-histaminergic blockade contribute to priapism and sedative side effects
   8. Dose is 50-200mg po qhs for sleep problems
4. Risperidone (Risperdal®)
   1. Added to baseline therapy in patients with inadequate response
   2. Dose 1mg qd, can be escalated to 2mg qd
   3. Improves overall response in patients on SSRI, SNRI, or buproprion
   4. Sleep disturbances most common side effect
5. Buspirone (Buspar®)
   1. Partial serotonin receptor 1A (5HT-1A) agonist
   2. Generally effective for anxiety symptoms, less as a monotherapy for depression
   3. Dose is 5mg po tid with escalation weekly to 20mg po tid or 30mg po bid
   4. May be added to SSRIs as "augmentation" with improved responses [30]
   5. May cause nausea, dizziness, lightheadedness, restlessness
   6. Side effects exacerbated with rapid dose escalation
   7. Does not cause sexual dysfunction but compliance is generally inferior to other agents [30]
6. MAO B Inhibitors (MAO-I)
   1. Newer agents are specific inhibitors of Type B monoamine oxidase
   2. In general, these agents should be used ONLY for resistant severe depression
   3. They prevent degradation of many bioactive amines
   4. May cause hypertensive crisis when taken with other bioactive amine compounds
   5. This includes pseudoephedrine, phenylephrine (common decongestants) and Levodopa
   6. Must avoid tyramine rich foods or beverages
   7. Must wait 2 weeks after stopping most other antidepressants before starting MAO-I's
   8. Must wait 6 weeks after stopping fluoxetine (due to long half life) before using MAO-I's
   9. Agents include Phenelzine (Nardil®), Tranylcypromine (Parnate®)
   10. Selegiline transdermal (Emsam®) appears better tolerated than oral (6mg/24 hr patch) and is FDA approved in major depression (usually used in resistant cases) [55]
7. MAO A Inhibitors [24]
   1. Reversible: Moclobemide (Auronix®), Medifoxamine (Cledial®), Toloxatone (Humoryl®)
   2. Reversible agents not yet approved in USA
8. Saint John's Wart (Hypericum) [32]
   1. Common name for flowering plant Hypericum perforatum
   2. Multiple active agents include naphthodianthrones, flavenoids, floroglucinols, others
   3. Hypericin, a napthodianthrone, is probably most important ingredient
   4. Clearly has activity better than placebo for mild or moderate (not major) depression
   5. However, direct comparisons with standard doses of SSRIs and TCAs have not been done
   6. Activity similar to 50-100mg/d (low dose) of imiprimine for moderate depression
   7. Efficacy (<15%) similar to placebo in major depression [32,33]
   8. Concern about other ingredients in these preparations
   9. In addition, Hypericum induces cytochrome P450 enzymes, altering drug metabolism
   10. May be of some benefit only in mild depression
9. S-Adenosyl Methionine (SAMe) [34]
   1. Endogenous compound used as methyl donor
   2. Pharmacologic doses (~1600mg/day) studied in depression
   3. Clinical trials were of short duration and failed to prove utility
   4. Quality and purity of SAMe preparations are questionable
10. Repetitive Transcranial Magnetic Stimulation (rTMS) [35]
    1. Experimental treatment for depression
    2. Induction of small electrical currents in cortical neurons by magnetic field
    3. Apply over dorso-lateral pre-frontal cortex
    4. May influence specific neural pathway
    5. Well tolerated therapy
11. Other Agents in Development [24]
    1. Gabamimetics: fengabine, GABA-A and GABA-B receptor agonists
    2. Dopamine Antagonists: amisulpride, sulpiride, other antipsychotics
    3. Minaprine (Cantor®) - increases serotonergic, cholingeric, dopaminergic neurotransmission

E. Electroconvulsive Therapy (ECT) [31,37,38]

1. Indications
   1. Therapy of choice in severe depression, particularly in hospitalized patients
   2. Need for rapid response: suicide risk, psychosis
   3. Failure to respond to antidepressant medications
   4. Good response to previous ECT
2. Mechanism
   1. Application of electricity to scalp to induce seizure activity
   2. Increases cortical GABA concentration
   3. Enhances serotonergic function, normalize HPA axis (cortisol regulation)
3. Efficacy
   1. More effective than drug therapy, particularly at higher electrical doses of ECT
   2. Remission rate ~75% after short course of ECT during acute episode of MDD
   3. By week 4 of treatment, ~65% remission rate
   4. One or two treatments per week probably as effective as three treatments / week
   5. Bilateral ECT more effective than unipolar ECT but with greater cognitive effects
   6. Six to 9 treatments are usually required for full restoration
4. Side Effects
   1. Most common persistent side effect is retrograde amnesia
   2. Anterograde amnesia typically resolves soon after ECT is completed
   3. Main side effects are cognitive with post-ictal confusional state, usually resolves within 1 hour
   4. Brief pulse stimuli or unilateral rather than bilateral electrodes reduce cognitive effects
   5. Prolonged seizures during ECT can occur but are rare
5. Duration of Efficacy
   1. ECT is very effective during treatment, but nearly all patients relapse within 6 months of stopping treatments unless pharmacotherapy is instituted [39]
   2. ECT should be followed by continuation treatment with pharmacotherapy
   3. Pharmacotherapy with nortriptyline ± lithium has been advocated [39]
6. No absolute contraindications to ECT [31]

F. Treatment Resistant Major Depression [3,13,25,41]

1. Patients with partial or nonresponse to SSRI, buproprion, nefazodone, OR venlafaxine
2. Causes of Treatment Resistant Depression (TRD) [25]
   1. In patients with partial or nonresponse to SSRI, buproprion, nefazodone, OR venlafaxine
   2. ~45% of patients treated initially are nonresponders
   3. Causes include:
   4. Inadequate treatment: underdosing, poos adherence, drug interactions
   5. Substance abuse (concomitant)
   6. Cognitive impairment and/or neurological disease
   7. Incorrect diagnosis: psychosis, dementia
   8. Need for adjunctive psychotherapy or behavioral cognitive therapy
3. TCA should be tried when appropriate usually after SSRI and SNRI
4. Combination of SSRI + another agent should be tried next
   1. Add on OR
   2. Add TCA OR
   3. Add stimulant OR
   4. Adding a low dose of antipsychotic may be beneficial
5. SSRI + low dose of atypical antipsychotic such as olanzapine is often effective [25]
   1. Particularly effective in psychotic depression
   2. FDA approved fluoxetine+olanzapine (Symbyax®) for bipolar depression
   3. In monopolar major depression, antipsychotic may be tapered after 4-6 months
6. Lithium added to classic antidepressants (600-800mg/d for >1 week) increases treatment response to up to 50% in refractory depression [42]
7. Lamotrigine (Lamictal®) or valproate can be added to SSRIs to improve outcomes [3]
8. Unclear if combination therapy is superior to increasing initial drug to very high levels [41]
9. Vagus Nerve Stimulation [51]
   1. May be effective in some patients with severe, chronic, treatment-resistant depression
   2. No statistical efficacy in 10 week randomized trial but some indications of activity
   3. FDA issued approvable letter for treatment-resistant depression
   4. Already approved for refractory epilepsy
10. For poor response to combination drug therapy, consider ECT
11. Cognitive therapy reduced suicide attempts from 41% (control) to 24% within 18 months of initial suicide attempt [52]

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