1. Major Depressive Disorder
Rowa’ Al-Ramahi

2. CLINICAL PRESENTATION
Emotional symptoms may include diminished ability to experience pleasure, loss of interest in usual activities, sadness, pessimistic outlook, crying spells, hopelessness, anxiety (present in almost 90% of depressed outpatients), feelings of guilt, and psychotic features (e.g., auditory hallucinations, delusions).

3. Physical symptoms may include fatigue, pain (especially headache), sleep disturbance, appetite disturbance (decreased or increased), loss of sexual interest, and GI and cardiovascular complaints (especially palpitations).

4. Intellectual or cognitive symptoms may include decreased ability to concentrate or slowed thinking, poor memory for recent events, confusion, and indecisiveness.
Psychomotor disturbances may include psychomotor retardation (slowed physical movements, thought processes, and speech) or psychomotor agitation. 4

5. DIAGNOSIS
Major depression is characterized by one or more episodes of major depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders.
Symptoms must have been present nearly every day for at least 2 weeks. Patients with major depressive disorder may have one or more recurrent episodes of major depression during their lifetime.

6. DIAGNOSIS
When a patient presents with depressive symptoms, it is necessary to investigate the possibility of a medical-, psychiatric-, and/or drug-induced cause.
Depressed patients should have a medication review, physical examination, mental status examination, a complete blood count with differential, thyroid function tests, and electrolyte determinations. 6

7. DESIRED OUTCOME
The goals of treatment of the acute depressive episode are to
eliminate or reduce the symptoms of depression
minimize adverse effects
ensure compliance with the therapeutic regimen
facilitate a return to a premorbid level of functioning
and prevent further episodes of depression.

8. NONPHARMACOLOGIC TREATMENT
If the depressive disorder is of mild to moderate severity, psychotherapy may be the first line therapy. The efficacy of psychotherapy and antidepressants is considered to be additive.
Psychotherapy alone is not recommended for the acute treatment of patients with severe and/or psychotic major depressive disorders.

9. For uncomplicated nonchronic major depressive disorder, combined treatment may provide no unique advantage. Cognitive therapy, behavioral therapy, and interpersonal psychotherapy appear to be equal in efficacy.

10. Electroconvulsive therapy (ECT) is a safe and effective treatment for major depressive disorder. It is considered when a rapid response is needed, risks of other treatments outweigh potential benefits, there has been a poor response to drugs, and the patient expresses a preference for ECT.

11. A rapid therapeutic response (10 to 14 days) has been reported
A rapid therapeutic response (10 to 14 days) has been reported. Relative contraindications include increased intracranial pressure, cerebral lesions, recent myocardial infarction, recent intracerebral hemorrhage, bleeding, and otherwise unstable vascular conditions.

12. Adverse effects of ECT include confusion, memory impairment (retrograde and anterograde), prolonged apnea, treatment emergent mania, headache, nausea, muscle aches, and cardiovascular dysfunction. Relapse rates during the year following ECT are high unless maintenance antidepressants are prescribed.
Bright light therapy (i.e., the patient looking into a 10,000-lux intensity light box for about 30 min/day) may be used for patients with seasonal affective disorder and as adjunctive use for major depression.

13. PHARMACOLOGIC THERAPY
In general, antidepressants are equal in efficacy in groups of patients when administered in comparable doses.
Factors that influence the choice of antidepressant include the patient’s history of response, history of familial response, concurrent medical conditions, presenting symptoms, potential for drug–drug interactions, comparative side-effect profiles of various drugs, patient preference, and drug cost.
Between 65% and 70% of patients with major depression improve with drug therapy.

14. Psychotically depressed individuals generally require either ECT or combination therapy with an antidepressant and an antipsychotic agent.
The acute phase of treatment lasts 6 to 10 weeks, and the goal is remission (i.e., absence of symptoms).
The continuation phase lasts 4 to 9 months after remission. The goal is to eliminate residual symptoms or prevent relapse.
The maintenance phase lasts at least 12 to 36 months, and the goal is to prevent recurrence of a separate episode of depression.

15. Some clinicians recommend lifelong maintenance therapy for persons at greatest risk for recurrence (i.e., persons younger than 40 years with two or more prior episodes and persons of any age with three or more prior episodes).
Educating the patients and their support systems regarding the delay in antidepressant effects (typically 2 to 4 weeks) and the importance of adherence should occur before therapy is started and throughout treatment.

16. The SSRIs inhibit the reuptake of 5-HT into the presynaptic neuron
The SSRIs inhibit the reuptake of 5-HT into the presynaptic neuron. They are generally chosen as first line antidepressants because of their safety in overdose and improved tolerability compared to earlier agents.
TCAs are effective for all depressive subtypes, but their use has diminished because of the availability of equally effective therapies that are safer on overdose and better tolerated. In addition to inhibiting the reuptake of NE and 5- HT, they also block adrenergic, cholinergic, and histaminergic receptors.

17. The MAOIs phenelzine and tranylcypromine increase the concentrations of NE, 5-HT, and DA within the neuronal synapse through inhibition of the monoamine oxidase (MAO) enzyme system. Both drugs are nonselective inhibitors of MAO-A and MAO-B. Selegiline is available as a transdermal patch for treatment of major depression. It inhibits MAO-A and MAO-B in the brain, but has reduced effects on MAO-A in the gut.

18. The triazolopyridines trazodone and nefazodone are antagonists at the 5- HT2 receptor and inhibit the reuptake of 5-HT. They can also enhance 5- HT1A neurotransmission. They have negligible affinity for cholinergic and histaminergic receptors. An extended release preparation of trazodone was recently approved. Nefazodone carries black box warning for liver failure.
Bupropion’s most potent neurochemical action is blockade of DA reuptake; it blocks the reuptake of NE to a lesser extent.

19. The serotonin-norepinephrine reuptake inhibitors include venlafaxine, Desvenlafaxine and duloxetine.
Maprotiline and amoxapine are inhibitors of NE reuptake, with less effect on 5-HT reuptake.
Mirtazapine enhances central noradrenergic and serotonergic activity through the antagonism of central presynaptic α2-adrenergic autoreceptors and heteroreceptors. It also antagonizes 5-HT2 and 5-HT3 receptors & blocks histamine receptors.

20. St. John’s wort, an herbal nonprescription medication containing hypericum, which shows mixed results regarding efficacy. It is associated with several drug–drug interactions. Its potency, purity, and manufacture are not regulated by the FDA.
Because depression is a potentially life- threatening disease, all antidepressant treatments should be overseen by a trained healthcare professional.

21. Adverse Effects
Tricyclic Antidepressants and Other Heterocyclics
Anticholinergic side effects (e.g., dry mouth, blurred vision, constipation, urinary retention, tachycardia, memory impairment, and delirium) and sedation are more likely to occur with the tertiary amine TCAs than with the secondary amine TCAs.
Desipramine is associated with an increased risk of death in patients with a family history of sudden cardiac death, cardiac dysrhythmias or cardiac conduction disturbances.

22. Orthostatic hypotension and resultant syncope, a common and potentially serious adverse effect of the TCAs, occurs as a result of α1- adrenergic antagonism. Additional side effects include cardiac conduction delays and heart block, especially in patients with preexisting conduction disease.
Other side effects that may lead to noncompliance include weight gain and sexual dysfunction.

23. Abrupt withdrawal of TCAs (especially high doses) may result in symptoms of cholinergic rebound (e.g., dizziness, nausea, diarrhea, insomnia, restlessness).
Amoxapine is a demethylated metabolite of loxapine and, as a result of its postsynaptic receptor DA-blocking effects, may be associated with extrapyramidal side effects.
Maprotiline, a tetracyclic drug, causes seizures at a higher incidence than do standard TCAs and is contraindicated in patients with a history of seizure disorder. The ceiling dose is considered to be 225 mg/day.

24. Venlafaxine may cause a dose-related increase in diastolic blood pressure. Dosage reduction or discontinuation may be necessary if sustained hypertension occurs. Other side effects are similar to those associated with the SSRIs (e.g., nausea and sexual dysfunction).
Duloxetine the most common side effects are nausea, dry mouth, constipation, decreased appetite, insomnia, and increased sweating.

25. The SSRIs produce fewer sedative, anticholinergic, and cardiovascular adverse effects than the TCAs and are less likely to cause weight gain than the TCAs. The primary adverse effects include nausea, vomiting, diarrhea, headache, insomnia, fatigue, and sexual dysfunction. A few patients have anxiety symptoms early in treatment.

26. Triazolopyridines
Trazodone and nefazodone cause minimal anticholinergic effects. Sedation, dizziness, and orthostatic hypotension are the most frequent dose limiting side effects.
Priapism occurs rarely with trazodone use (1 in 6,000 male patients). Surgical intervention may be required, and impotence may result.

27. A black box warning for life-threatening liver failure was added to the prescribing information for nefazodone. Treatment with nefazodone should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. 27

28. Aminoketone
The occurrence of seizures with bupropion is dose related and may be increased by predisposing factors (e.g., history of head trauma or CNS tumor). At the ceiling dose (450 mg/day), the incidence of seizures is 0.4%. Other side effects include nausea, vomiting, tremor, insomnia, dry mouth, and skin reactions. It is contraindicated in patients with bulimia or anorexia nervosa.
Mirtazapine’s most common adverse effects are somnolence, weight gain, dry mouth, and constipation.

29. Monoamine Oxidase Inhibitors
The most common adverse effect of MAOIs is postural hypotension (more likely with phenelzine than tranylcypromine), which can be minimized by divided-daily dosing. Anticholinergic side effects are common but less severe than with the TCAs. Phenelzine causes mild to moderate sedating effects, but tranylcypromine is often stimulating, and the last dose of the day is administered in early afternoon. Sexual dysfunction in both genders is common. Phenelzine has been associated with hepatocellular damage and weight gain.

30. Hypertensive crisis is a potentially fatal adverse reaction that can occur when MAOIs are taken concurrently with certain foods, especially those high in tyramine, and with certain drugs.
Symptoms of hypertensive crisis include occipital headache, stiff neck, nausea, vomiting, sweating, and sharply elevated blood pressure. Hypertensive crisis may be treated with agents, such as captopril. Education of patients taking MAOIs regarding dietary and medication restrictions is critical.

31. PHARMACOKINETICS
The major metabolic pathways of the TCAs are demethylation, hydroxylation, and glucuronide conjugation. Metabolism of the TCAs appears to be linear within the usual dosage range, but dose-related kinetics cannot be ruled out in the elderly.

32. Mirtazapine is primarily eliminated in the urine.
The SSRIs, with the possible exception of citalopram and sertraline, may have a nonlinear pattern of drug accumulation with chronic dosing.
Mirtazapine is primarily eliminated in the urine.
Factors reported to influence TCA plasma concentrations include disease states (e.g., renal or hepatic dysfunction), genetics, age, cigarette smoking, and concurrent drug administration. Similarly, hepatic impairment, renal impairment, and age have been reported to influence the pharmacokinetics of SSRIs.

33. In acutely depressed patients, there is a correlation between antidepressant effect and plasma concentrations for some TCAs.
Some indications for plasma level monitoring include inadequate response, relapse, serious or persistent adverse effects, use of higher than standard doses, suspected toxicity, elderly patients, children and adolescents, pregnant patients, patients of African or Asian descent (because of slower metabolism), cardiac disease, suspected noncompliance, suspected pharmacokinetic drug interactions, and changing brands.

34. Plasma concentrations should be obtained at steady state, usually after a minimum of 1 week at constant dosage. Sampling should be done during the elimination phase, usually in the morning, 12 hours after the last dose. Samples collected in this manner are comparable for patients on once daily, twice-daily, or thrice-daily regimens.

35. DRUG–DRUG INTERACTIONS
The very slow elimination of fluoxetine and norfluoxetine makes it critical to ensure a 5-week washout after fluoxetine discontinuation before starting an MAOI. Potentially fatal reactions may occur when any SSRI or TCA is coadministered with an MAOI.

36. Increased plasma concentrations of TCAs and symptoms of toxicity may occur when fluoxetine and paroxetine are added to a TCA regimen.
The combination of an SSRI with another 5-HT augmenting agent can lead to the serotonin syndrome, which is characterized by symptoms such as clonus, hyperthermia, and mental status changes.

37. The ability of an SSRI, or any antidepressant, to inhibit or induce the activity of the cytochrome P450 (CYP450) enzymes can be a significant contributory factor in determining its capability to cause a pharmacokinetic drug–drug interaction.
The drug interaction literature should be consulted for detailed information concerning any real or potential drug interaction involving any psychotherapeutic agent.

38. SPECIAL POPULATIONS Elderly Patients
Prominent symptoms of depression in the elderly are loss of appetite, cognitive impairment, sleeplessness, anergia, fatigue, and loss of interest in and enjoyment of the normal pursuits of life.
The SSRIs are often selected as first-choice antidepressants in elderly patients.
Bupropion and venlafaxine may also be chosen because of their milder anticholinergic and less frequent cardiovascular side effects.

39. Children and Adolescents
Symptoms of depression in childhood include boredom, anxiety, failing adjustment, and sleep disturbance.
Data supporting efficacy of antidepressants in children and adolescents are sparse. Fluoxetine is the only antidepressant that is FDA approved for treatment of depression in patients less than 18 years of age.

40. The FDA has established a link between antidepressant use and suicidality (suicidal thinking and behaviors) in children, adolescents, and young adults 18 to 24 years old. All antidepressants carry a black box warning providing cautions in the use of all antidepressants in this population, and the FDA also recommends specific monitoring parameters. The clinician should consult the FDA-approved labeling or the FDA website for additional information. However, several retrospective longitudinal reviews of the use of antidepressants in children found no significant increase in the risk of suicide attempts or deaths 40

41. Several cases of sudden death have been reported in children and adolescents taking desipramine. A baseline electrocardiogram (ECG) is recommended before initiating a TCA in children and adolescents, and an additional ECG is advised when steady-state plasma concentrations are achieved. TCA plasma concentration monitoring is critical to ensure safety.

42. Pregnancy
As a general rule, if effective, nondrug approaches are preferred when treating depressed pregnant patients. One study showed that pregnant women who discontinued antidepressants were five times more likely to relapse during their pregnancy than were women who continued treatment.
No major teratogenic effects have been identified with the SSRIs or TCAs. However, evaluations to date suggest a possible association of fluoxetine with low birth weight and respiratory distress.

43. Another study reported a sixfold greater likelihood of the occurrence of persistent pulmonary hypertension of newborn infants exposed to an SSRI after the twentieth week of gestation.
The risks of untreated depression in pregnancy should be considered. These included low birth weight, maternal suicidality, potential for hospitalization or marital discord, poor prenatal care, and difficulty caring for other children. 43

44. REFRACTORY PATIENTS
Most “treatment-resistant” depressed patients have received inadequate therapy. Issues to be considered in patients who have not responded to treatment include the following: (1) Is the diagnosis correct? (2) Does the patient have a psychotic depression? (3) Has the patient received an adequate dose and duration of treatment? (4) Do adverse effects preclude adequate dosing? (5) Has the patient been compliant with the prescribed regimen? (6) Was treatment outcome measured adequately? (7) Is there a coexisting or preexisting medical or psychiatric disorder? (8) Was a stepwise approach to treatment used? (9) Are there other factors that interfere with treatment?

45. The STAR*D study showed that one in three depressed patients who previously did not achieve remission with an antidepressant became symptom-free with the help of an additional medication (e.g., bupropion sustained release), and one in four achieved remission after switching to a different antidepressant (e.g., venlafaxine XR).
The current antidepressant may be stopped, and a trial initiated with an agent of unrelated chemical structure (e.g., mirtazapine or nortriptyline). 45

46. Alternatively, the current antidepressant may be augmented (potentiated) by the addition of another agent (e.g., lithium, T3), or another antidepressant can be added. An atypical antipsychotic can be used to augment antidepressant response.
The practice guideline of the American Psychiatric Association recommends that after 6 to 8 weeks of antidepressant treatment, partial responders should consider changing the dose, augmenting the antidepressant, or adding psychotherapy or ECT. For those with no response, options include changing to another antidepressant or the addition of psychotherapy or ECT 46

47. A 6-week antidepressant trial at a maximum dosage is considered an adequate trial. Patients must be told about the expected lag time of 2 to 4 weeks before the onset of antidepressant effect.
Elderly patients should receive one-half the initial dose given to younger adults, and the dose is increased at a slower rate. The elderly may require 6 to 12 weeks of treatment to achieve the desired antidepressant response.
To prevent relapse, antidepressants should be continued at full therapeutic doses for 4 to 9 months after remission. 47

48. EVALUATION OF THERAPEUTIC OUTCOMES
Several monitoring parameters, in addition to plasma concentrations, are useful in managing patients. Patients must be monitored for adverse effects, remission of previously documented target symptoms, and changes in social or occupational functioning. Regular monitoring should be assured for several months after antidepressant therapy is discontinued.
Patients given venlafaxine should have blood pressure monitored regularly.
Patients older than age 40 years should receive a pretreatment ECG before starting TCA therapy, and follow-up ECGs should be performed periodically.

49. EVALUATION OF THERAPEUTIC OUTCOMES
Patients should be monitored for emergence of suicidal ideation after initiation of any antidepressant, especially in the first few weeks of treatment.
In addition to the clinical interview, psychometric rating instruments allow for rapid and reliable measurement of the nature and severity of depressive and associated symptoms. 49