Depression Treatment & Management

A wide range of effective treatments is available for major depressive disorder. Medication alone can relieve symptoms (see Medications), and brief psychotherapy (eg, cognitive-behavioral therapy, interpersonal therapy) has also been shown in clinical trials to be an effective treatment option, either alone or in combination with medication. However, the combined approach of medication and psychotherapy generally provides the patient with the quickest and most sustained response. In children and adolescents, pharmacotherapy is insufficient as the only treatment.

All antidepressants on the market are potentially effective. Usually, 2-6 weeks at a therapeutic dose level are needed to observe a clinical response. The choice of medication should be guided by anticipated safety and tolerability, which aid in compliance; physician familiarity, which aids in patient education and anticipation of adverse effects; and history of previous treatments. Often, treatment failures are caused not by clinical resistance but by medication noncompliance, inadequate duration of therapy, or inadequate dosing.

According to the 2008 American College of Physicians guideline (the most recent release of the guideline) on using second-generation antidepressants to treat depressive disorders, patient preferences should be given serious consideration when choosing the best course of pharmacotherapy for patients with depressive disorders. The patient may want to avoid use of a particular antidepressant if he or she had a previous negative experience with the drug.^[61]

The 2008 ACP guideline advises that treatment should be altered if the patient does not have an adequate response to pharmacotherapy within 6-8 weeks of the onset of therapy for major depressive disorder. Once satisfactory response is achieved, treatment should be continued for 4-9 months in patients with a first episode of major depression. In those who have had 2 or more episodes of depression, a longer course of treatment may prove beneficial.^[61]

Clinical experience indicates a complex interaction between neurotransmitter availability, receptor regulation and sensitivity, and affective symptoms in major depressive disorder. Drugs that produce only an acute rise in neurotransmitter availability, such as cocaine, do not have the efficacy over time that antidepressants do. Furthermore, an exposure of several weeks' duration to an antidepressant is usually necessary to produce a change in symptoms. This, together with preclinical research findings, implies a role for neuronal receptor regulation over time in response to enhanced neurotransmitter availability.

In 2011, the American Psychiatric Association (APA) updated its Practice Guideline for the Treatment of Patients with Major Depressive Disorder. The 2011 APA guideline emphasizes the need to customize a treatment plan for each patient based on a careful assessment of symptoms, including rating scale measurements administered by a clinician or the patient as well as an analysis of therapeutic benefits and side effects. Treatment should maximize patient function within specific and realistic goals. The initial modality should be based on clinical assessment, other disorders, stressors, patient preference, and reactions to previous treatment.^[62]

Selective serotonin reuptake inhibitors

Selective serotonin reuptake inhibitors (SSRIs) have the advantage of ease of dosing and low toxicity in overdose. SSRIs are greatly preferred over the other classes of antidepressants for the treatment of children and adolescents, and these agents are also the first-line medications for late-onset depression, due to their superior tolerability and comparatively more benign safety profile. This recommendation is supported by the 2011 APA guideline.^[62] Common adverse effects include gastrointestinal (GI) upset, sexual dysfunction, and changes in energy level (ie, fatigue, restlessness).

The SSRIs are thought to be not as worrisome in patients with cardiac disease, as they do not appear to exert any effect on blood pressure, heart rate, cardiac conduction, or cardiac rhythm; however, dose-dependent QT prolongation has been reported with citalopram. Because of the risk for QT prolongation, citalopram is contraindicated in individuals with congenital long QT syndrome and the dose should not exceed 40 mg/d.^{[63, 64]}

Because the adverse effect profile of SSRIs is less prominent than other agents, improved compliance is promoted. SSRIs include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro). Escitalopram has been shown to have superior efficacy to other antidepressants in the treatment of more severe depression,^[65] and it is at least as effective as SNRIs and better tolerated, even in severe depression.^[66]

Selective serotonin/norepinephrine reuptake inhibitors

Selective serotonin/norepinephrine reuptake inhibitors (SNRIs), which include venlafaxine (Effexor), desvenlafaxine (Pristiq), and duloxetine (Cymbalta), can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression. SNRIs also have an important role when used sequentially as second-line agents in patients who have not responded to SSRIs. Their use concurrently with other antidepressants may be more problematic. For example, the Combining Medications to Enhance Depression Outcomes (CO-MED) study found that combining extended-release venlafaxine plus mirtazapine may actually have a greater risk of adverse events and does not outperform monotherapy.^[67]

Safety, tolerability, and side effect profiles of SNRIs are similar to those of the SSRIs, with the exception that the SNRIs have been associated (rarely) with a sustained rise in blood pressure. Venlafaxine has been particularly associated with hyponatremia.

Atypical antidepressants

Atypical antidepressants effectively augment therapy in major depressive disorder, but they are associated with an increased risk for adverse effects. These agents include bupropion (Wellbutrin), mirtazapine (Remeron), and trazodone (Desyrel). Despite the increased risk for adverse effects, this group also shows low toxicity in overdose and may have an advantage over the SSRIs by causing less sexual dysfunction and GI distress.

Tricyclic antidepressants

Tricyclic antidepressants (TCAs) include amitriptyline (Elavil), nortriptyline (Pamelor), desipramine (Norpramin), clomipramine (Anafranil), doxepin (Sinequan), protriptyline (Vivactil), trimipramine (Surmontil), and imipramine (Tofranil). These agents have a long record of efficacy in the treatment of depression and have the advantage of lower cost. They are used less commonly at present because of the need to titrate the dose to a therapeutic level and because of their considerable toxicity in overdose.

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) are widely effective in a broad range of affective and anxiety disorders and include phenelzine (Nardil) and tranylcypromine (Parnate). Because of the risk of hypertensive crisis, patients on these medications must follow a low-tyramine diet. Other adverse effects can include insomnia, anxiety, orthostasis, weight gain, and sexual dysfunction.

St. John's wort

Although St. John's wort is considered a first-line antidepressant in many European countries, it has only recently gained popularity in the US. Uses include treatment of mild to moderate depressive symptoms. Research indicates that it acts as an SSRI and not as an MAOI, as previously believed. The dosage is 300 mg 3 times a day with meals to prevent GI upset. If no clinical response occurs after 3-6 months, encouraging the use of another medication is essential. In addressing the issue of alternative therapies for depression, the 2011 APA guideline noted that St. John's wort might be considered, but evidence for its effectiveness is modest, and more information is needed about its interaction with other drugs.^[62]

Psychodynamic psychotherapy, interpersonal therapy, cognitive-behavioral therapy, behavior therapy, family therapy, supportive psychotherapy, and group psychotherapy have all been used for the treatment of major depressive disorder, especially in the pediatric population. In mild cases, psychosocial interventions are often recommended as first-line treatments. The APA guideline supports this approach, but notes that combining psychotherapy with antidepressant medication may be more appropriate for patients with moderate to severe major depressive disorder.^[62]

Several factors appear to be related to the response to psychotherapy, including age at onset of depression, severity of depression, presence of comorbid psychiatric disorders (eg, anxiety, dysthymia, substance abuse), lack of support, parental psychopathology, family conflict, exposure to stressful life events, socioeconomic status, quality of treatment, therapist's expertise, and motivation of both patient and therapist. A combination of the particular elements of cognitive-behavioral therapy, interpersonal therapy, psychodynamic psychotherapy, and other psychotherapies may be brought together in the best interests of the patient.

Cognitive-behavioral therapy (CBT) is first-line treatment for depression that is directed and time limited, usually involving between 10 and 20 treatments. CBT was specifically designed to treat depression, and its use in treating major depressive disorder is based on the premise that patients who are depressed have a distorted view of themselves, the world, and the future. These cognitive distortions contribute to their depression and can be identified and counteracted with CBT.

CBT is effective in patients of all ages. It is particularly valuable for elderly patients, who may be more prone to problems or side effects with medications.^{[30, 68]} In children and adolescents, 4 studies have shown group CBT to be better than no intervention in the reduction of depressive symptoms and improvement of self-esteem. In fact, in most pediatric clinical samples, CBT was found to be superior to other manualized treatments, including relaxation training and family and supportive therapy. However, all clinical studies of CBT found a high rate of relapse on follow-up, suggesting the need for continuation treatment. Given the high rate of relapse and recurrence of depression, continuation therapy is recommended for all patients for at least 6-12 months.

Many clinicians find psychodynamic psychotherapy to be useful in the treatment of depression in youths. Psychodynamic psychotherapy can help youths understand themselves, identify feelings, improve self-esteem, change maladaptive patterns of behavior, interact more effectively with others, and cope with ongoing and past conflicts. However, although controlled studies using psychodynamic psychotherapy for the treatment of depression in children and adolescents are greatly needed, these studies are also particularly difficult to design and expensive to conduct.

Interpersonal therapy focuses on problem areas of grief, interpersonal roles, disputes, role transitions, and interpersonal difficulties. Mufson and Fairbanks found that interpersonal therapy may be useful in the acute treatment of adolescents with major depressive disorder, and that the rate of relapse is relatively low after acute interpersonal therapy treatment.^[69]

Electroconvulsive therapy (ECT) is used when a rapid antidepressant response is needed, when drug therapies have failed, when there is a history of good response to ECT, or when there is patient preference. This is a highly effective treatment for depression. Onset of action may be more rapid than that of drug treatments (see Medications), with benefit often seen within 1 week of commencing the treatment. ECT is particularly effective in the treatment of delusional depression, and it is the treatment of choice for patients who are psychotic or imminently suicidal or dangerous to themselves.

Although advances in brief anesthesia and neuromuscular paralysis have improved the safety and tolerability of ECT, this modality poses numerous risks, including those associated with general anesthesia, postictal confusion, and, more rarely, short-term memory difficulties. Especially in elderly patients, a preprocedure work-up should be undertaken and should examine cardiac and vascular risk, as the procedure places a high cardiovascular demand on the patient.

Transcranial magnetic stimulation has been FDA approved for the treatment of major depressive disorder, when the patient has failed less than 2 classes of antidepressants. Initial results suggest that it may be an effective intervention without the risks and adverse effects of ECT. Its efficacy in refractory cases has yet to be proven.

Vagus nerve stimulation has been FDA approved for use in treatment-resistant depression (see below), which was defined as failure of 4 or more adequate antidepressant treatments.

Bright light therapy (BLT) for seasonal affective disorder is used at an intensity of 10,000 lux for 30-90 minutes daily, usually within 1 hour of arising in the morning. Like any effective antidepressant, therapeutic light boxes have the potential to precipitate a manic episode in susceptible individuals. Other common adverse effects include eye irritation, restlessness, and transient headaches. These lamps are not a significant source of ultraviolet (UV) light. Conventional antidepressants, with or without BLT, also can be used to treat seasonal affective disorder.

Although broad-spectrum light exposure has long been in use for the treatment of seasonal affective disorder, there has been some evidence that this therapy may have some efficacy in nonseasonal depression or as an augmenting agent with antidepressant medication.

A meta-analysis examined the therapeutic effect of exercise in depressed individuals.^[70] This meta-analysis revealed a short-term (≤16 wk) small positive effect on depression scores, but no long-term benefit was realized. The authors felt that the evidence did not support the use of exercise for long-term benefits in clinically depressed individuals. The limited available evidence does not support using exercise as an “antidepressant.”

Deep brain stimulation and direct cortical stimulation are currently being used investigationally for treatment of patients with refractory depression.^[71]

In 67% of cases of depression, patients fail to remit with first-line therapy, according to Rush et al.^[72] Their Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial applied various treatment strategies with a final remission rate of 67%. Although the 2011 APA guidelines reviewed this study, it concluded that the generic medications used in the past are as effective as any other initial treatments.^[62]

Assessment of patients with treatment-resistant depression should include the following:

• Adequacy of medication dose, duration of treatment, and compliance
• Accuracy of diagnosis and possible medical conditions
• Possible comorbid psychiatric conditions such as substance abuse, anxiety disorders, or personality disorders

Assuming that the assessment of the diagnosis is correct, there are no significant complicating diagnoses, and the current treatment has been at a therapeutic dose for a sufficient amount of time, possible interventions for persistent symptoms can include the following^[62] :

• Increasing the medication dose to the maximum tolerated
• Changing to a different antidepressant
• Adding psychotherapy or more intensive care if not already completed
• Augmenting the current medication
• Considering the use of ECT

Aripiprazole (Abilify) is the first drug approved by the US Food and Drug Administration (FDA) for adjunctive treatment in major depressive disorder and the first drug to receive FDA approval for use in treatment-resistant depression.

Aripiprazole resulted in a 26% remission rate, versus 15% for placebo, in one study. Other placebo-controlled trials also support the use of adjunctive aripiprazole in treatment-resistant depression. In these studies, the addition of aripiprazole to an SSRI or SNRI regimen resulted in statistically significant reductions in remission rates.^{[73, 74, 75]}

In 38% of cases, patients did not have a treatment response over 6-12 weeks with bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, sertraline, trazodone, or venlafaxine, and 54% did not achieve remission with any of these agents, according to a 2007 research review by the Agency for Healthcare Research and Quality (AHRQ) in which these 12 second-generation antidepressants were compared.^[76]

In addition, there was no reliable way to predict whether an individual patient would respond to therapy. The average effectiveness of the antidepressants appeared similar, but the studies reviewed were not designed to test variation among patients’ responses to individual drugs. However, the AHRQ did find moderately strong evidence of differences among individual second-generation antidepressants with respect to onset of action and some measures (eg, sexual functioning) that could affect health-related quality of life.

The 2008 ACP guideline advises clinicians to choose second-generation antidepressants on the basis of adverse effects, cost, and patient preferences, since all these agents have comparable efficacy. Patient status, response to therapy, and adverse effects of antidepressants should be assessed within 1-2 weeks of starting therapy.^[61]

Augmentation combinations can include the following:

• Lithium (Eskalith, Lithane, Lithobid) plus any antidepressant
• Buspirone (BuSpar) plus a TCA or SSRI
• Triiodothyronine (Cytomel) added to any antidepressant
• A TCA added to an SSRI
• Methylphenidate (Ritalin) or dextroamphetamine (Dexedrine) added to any antidepressant other than an MAOI
• The addition of bright-light therapy to any antidepressant

In a meta-analysis, Fournier et al found that the magnitude of medication superiority over placebo increased with increases in baseline depression severity, crossing the threshold for a clinically significant difference at a baseline HDRS score of 25. Patients exhibiting very severe depression showed a substantial benefit with use of antidepressant drugs compared with placebo. The researchers evaluated 6 studies representing 718 patients to evaluate the benefit of antidepressant drugs compared with placebo according to initial symptom severity in patients with depression. In patients with mild or moderate depression symptoms, benefit of antidepressant medication compared with placebo was measured as minimal or nonexistent.^[77]

Studies on the use of medications for youths with major depressive disorder are few, and some have methodologic problems. Additionally, very few pharmacokinetics studies have been performed in children, and of those few, the trials have focused on the effects of TCAs, with few studies addressing SSRIs.

The clinician needs to inform parents and patients about adverse effects, the dose, the timing of therapeutic effect, and the danger of overdose, particularly with TCAs, before initiating pharmacologic treatment. Parents should take responsibility for medication storage and administration, especially with younger children and children at risk for suicide. Because of the potential of the TCAs to induce a fatal overdose, the clinician must carefully determine the exact amount of medication to be prescribed at each appointment and plasma levels should be monitored to measure compliance and to avoid toxicity.

The TCAs require a baseline electrocardiogram (ECG), resting blood pressure, and pulse rate. Weight should also be frequently documented. No laboratory tests are currently indicated before or during the administration of the SSRIs. No other tests are indicated in a healthy child before starting antidepressants.

Although open studies using TCAs suggest their usefulness in treating youths with major depressive disorder, several randomized controlled studies have shown 50-60% response to both TCAs (nortriptyline, desipramine, amitriptyline) and placebo. Consider these results with caution because of methodologic limitations, including small sample sizes, short-duration trials, and inclusion of patients with mild depression and comorbid disorders that may have had good responses to placebo.

TCAs are no longer considered the first-line treatment for youths with depressive disorders; however, individual cases may respond better to TCAs than to other medications. TCAs may also be useful for youths with comorbid attention deficit hyperactivity disorder (ADHD), enuresis, and narcolepsy, as well as for augmentation strategies.

Because of reports that SSRIs are effective for the treatment of youths with MDD and reports that SSRIs have a relatively safe adverse effect profile, very low lethality after overdose, and only once daily administration, the clinician may support the use of the SSRIs as first-line medications in pediatric patients.

A 70-90% response rate to SSRIs has been reported in the treatment of adolescents with major depressive disorder in studies such as those by Leonard et al^[78] and Rey-Sanchez and Gutierrez-Casares.^[79]

Children and adolescents responded significantly better to fluoxetine (58%) than to placebo (32%), according to Emslie et al in an 8-week double-blind study of the treatment of a large sample of youths with major depressive disorder.^[80] However, only 31% of children achieved full remission. A possible explanation for the partial response in these young patients is that the effective treatment may involve variation in dose or length of treatment. Also, the ideal treatment likely involves a combination of pharmacologic and psychosocial interventions.

Except for lower initial doses, the administration of SSRIs in children and adolescents is similar to the treatment protocols used for adult patients. The clinician should treat patients with adequate and tolerable doses for at least 4 weeks. At 4 weeks, if the patient has not shown even minimal improvement, the clinician should consider increasing the dose. If, at this time, the patient shows improvement, the dose can be continued for at least 6 weeks. However, if no improvement is apparent at 6 weeks, other treatment strategies should be considered.

The clinician must cautiously apply the above recommendation; whether longer trials with SSRIs increase the number of pediatric patients with late improvement is not clear. The SSRIs possess a relatively flat dose-response curve, suggesting that maximal clinical response may be achieved at minimum effective doses; therefore, adequate time must be allowed for clinical response and frequent early dose adjustments must be avoided. Blood levels are rarely indicated in clinical settings, but they may help clarify concerns about toxicity or medical compliance.

The adverse effects of all SSRIs in children are similar to those in adults; they are dose-dependent and may subside with time. SSRIs may induce mania, hypomania, and behavioral activation, in which patients become impulsive, silly, agitated, and daring. Other adverse effects include GI symptoms, restlessness, diaphoresis, headaches, akathisia, bruising, and changes in appetite, sleep, and sexual functioning. The long-term adverse effects of SSRIs are not yet known.

Physicians are advised to be aware of the following information and to use appropriate caution when considering treatment with SSRIs in the pediatric population.

In December 2003, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) issued an advisory that most SSRIs are not suitable for use by persons younger than 18 years for treatment of "depressive illness." After review, MHRA decided that the risks to pediatric patients outweigh the benefits of treatment with SSRIs, except for fluoxetine, which appears to have a positive risk-benefit ratio in the treatment of depressive illness in patients younger than 18 years.

In October 2003, the FDA issued a public health advisory regarding reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder. This advisory reported suicidality (both ideation and attempts) in clinical trials of various antidepressant drugs in pediatric patients. The FDA has asked that additional studies be performed, because suicidality occurred in both treated and untreated patients with major depression and, thus, could not be definitively linked to drug treatment.

In September 2004, the results of an FDA analysis suggested that the risk of emergent suicidality in children and adolescents taking SSRIs was real. The FDA advisors (Columbia University) recommended the following:

• A "black-box" warning label be placed on all antidepressants, indicating that they increase the risk of suicidal thinking and behavior (suicidality)
• A patient information sheet (“Medication Guide”) be provided to the patient and their caregiver with every prescription
• The results of controlled pediatric trials of depression be included in the labeling for antidepressant drugs

The Psychopharmacologic Drugs and Pediatric Advisory Committees recommended that the products not be contraindicated in the US, because access was important for those who could benefit from them. For more information, see the FDA Statement on Recommendations of the Psychopharmacologic Drugs and Pediatric Advisory Committees.

This remains a controversial issue. Some studies have shown that the FDA warnings regarding suicide in children on antidepressants may have had the unintended result of a decrease in the rates of diagnosis and treatment of depression as well as dosing adjustments by physicians. It has also been noted that monitoring of these patients did not increase following the warnings.^{[81, 82]}

An observational study by Leon et al followed 757 patients over a 27-year period that included participants with psychiatric and other medical comorbidity and those receiving acute or maintenance therapy, polypharmacy, or no psychopharmacologic treatment at all.^[83] The results suggest antidepressants were associated with a significant reduction in the risk of suicidal behavior; however, clinicians must closely monitor patients when an antidepressant is initiated.

Other studies have argued that a decline in youth suicide rates coincided, to a striking extent, with significant increases in the prescription of antidepressants (mostly SSRIs) to adolescents.^{[84, 85, 86]} The Treatment for Adolescents with Depression Study (TADS) lends support for fluoxetine's efficacy in adolescent depression, notably the combined use of fluoxetine with cognitive-behavioral therapy.^[87] Data from the TADS study also suggested a possible protective effect of cognitive-behavioral therapy against suicidality when used in combination with fluoxetine.

Additionally, a study of more than 65,000 children and adults treated for depression between by the Group Health Cooperative in Seattle found that suicide risk declines, not rises, with the use of antidepressants.^[88] This is the largest study to date to address this issue.

Women who plan to breastfeed must be informed that antidepressants, like all psychotropic medications, are secreted into breast milk. Concentrations in breast milk vary widely.^[89] Data on the use of TCAs, fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) during breastfeeding are encouraging, and serum antidepressant levels in the breastfed infant are either low or undetectable. Reports of toxicity in breastfed infants are rare, although the long-term effects of exposure to trace amounts of medication are not known.^[54]

Geriatric psychopharmacology follows the tenet of "start low, go slow, but go," which is based on belief that elderly patients respond to such agents more slowly than younger patients and the fact that older patients tend to have a higher rate of side effects and adverse events due to drug-drug or drug-disease state interactions. Most classes of medications have been associated with an increased fall risk in elderly patients, especially the frail elderly. Furthermore, results from a study by Andreescu et al suggest that high levels of worry in elderly patients with depression were associated with slower response to pharmacotherapy and earlier recurrence.^[90]

Based on the above, start antidepressant medications at a lower dose (oftentimes half the usual dose) in the elderly, and titrate more slowly than in younger adults. Furthermore, customary practice is to give the elderly patient a longer trial (12 wk vs customary 6-8 wk) before increasing the dose or changing the medication or labeling it a failure. However, the need to wait 12 weeks remains a point of controversy and is undergoing more research.

In the elderly, drug-drug interactions are a concern with particular SSRIs because polypharmacy is common in this age group. Of the SSRIs, the likelihood of drug-drug interaction is highest with fluoxetine, paroxetine, and fluvoxamine. The specific interactions of these medications and medications commonly used in the elderly (eg, certain antibiotics, warfarin) are well established and available in many reference books.

SSRIs should only be used in the elderly with consideration by a physician familiar with these types of medications. The SSRIs that offer a lower likelihood of drug-drug interactions include escitalopram, citalopram, and sertraline. These medications should be used as first-line treatment in the elderly or in patients where drug-drug interaction is a concern. Gastrointestinal side effects, including nausea, which can lead to weight loss, can be a problem in the elderly with use of SSRIs. Oftentimes the nausea is short lived, but when it is not, further options should be evaluated.

Few studies of the treatment of refractory depression in geriatric populations are available. Cooper et al recently reviewed 14 studies of the management of treatment-refractory depression (defined as “failure to respond to at least one course of treatment for depression during the current illness episode”) in patients aged 55 years and older. Although they noted ”half of the participants responded to pharmacological treatments” and concluded that this observation indicated “the importance of managing treatment-refractory depression actively,” they also noted most were open-label studies and had other significant methodological problems, and none were double-blind randomized placebo-controlled trials. The value of pharmacological treatment of refractory depression in geriatric parents remains uncertain.^[91]

Although avoiding the use of medication during pregnancy is preferable, the benefits of prompt medical treatment of major depressive disorder may often outweigh the risks of exposure of the fetus to an antidepressant. Still, the APA guideline supports psychotherapy as the first choice of therapy for pregnant women with mild depression.^[62] One meta-analysis points to the possible risks of untreated peripartum depression, which include increased risk of preterm birth, low birth weight, and intrauterine growth restriction.^[92] Although untested in controlled trials, there is no clear evidence that available antidepressants are teratogenic. In severe depression during pregnancy, especially in cases of psychosis, agitation, or severe retardation, ECT may be the safest and quickest treatment option. In these cases, the APA guideline recommends antidepressant medication.^[62]

Conflicting evidence exists regarding use of SSRIs during pregnancy and increased risk of persistent pulmonary hypertension of the newborn. An initial Public Health Advisory in 2006 was based on a single retrospective study published study; since then, there have been conflicting findings from new studies, making it unclear whether use of SSRIs during pregnancy can cause PPHN.^[93]

The FDA has reviewed the results of an additional new study and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. The FDA is advising health care professionals not to alter their current clinical practice of treating depression during pregnancy and to report any adverse events to the FDA MedWatch program.^[94]

Principles of treatment for postpartum major depressive disorder are the same as for depression during any other time of life. The patient should be assessed for danger to herself or to her children, as well as for other symptoms such as psychosis or substance abuse. Most antidepressants probably can be used safely during breastfeeding; however, this has not been studied thoroughly, and the same risk-benefit considerations should be applied as when treating depression during pregnancy.^[95]

Postpartum blues are typically mild and resolve spontaneously; no specific treatment is required, other than support and reassurance. Principles of treatment for postpartum major depressive disorder are the same as for depression during any other time of life. Earlier initiation of treatment is associated with better prognosis.^[96] If the woman is suffering the first episode of depression, 6-12 months of treatment is recommended. For women with recurrent major depression following pregnancy, long-term maintenance treatment with an antidepressant is indicated.^[97]

If suicidality is present, hospitalization with the patient's consent or via emergency commitment should be undertaken unless there are clear-cut means to ensure the patient's safety while outpatient treatment is begun. A child who is suicidal or has made an attempt at suicide should be admitted to a protected environment until all medical and social services can be employed.

In addition to suicidal or homicidal ideation, indications for psychiatric hospitalization include the following:

• Severe depression
• Psychotic depression
• Inability to care for self (ie, inability to provide basic needs such as eating, drinking, and other activities of daily living)
• Failing medical status due to depression

Dietary restrictions are necessary only when prescribing MAOIs. Foods high in tyramine, which can produce a hypertensive crisis in the presence of MAOIs, should be avoided. These foods include soy sauce, sauerkraut, aged chicken or beef liver, aged cheese, fava beans, air-dried sausage and similar meats, pickled or cured meat or fish, overripe fruit, canned figs, raisins, avocados, yogurt, sour cream, meat tenderizer, yeast extracts, caviar, and shrimp paste. Beer and wine also should be avoided.

Physical activity and exercise contribute to recovery from major depressive disorder. Patients should be counseled regarding stress reduction.

The incidence of SSRI-induced hyponatremia has been increasing and is estimated to occur in up to 25% of the elderly taking SSRIs. Risk factors include increased age, female gender, smoking, low body weight, tumors, respiratory or CNS illnesses, previous episodes of hyponatremia, and being on other medications (particularly diuretics).^[98] The mechanism is through the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), resulting in an euvolemic hyponatremia with low serum and high urine osmolalities. The hyponatremia generally starts within 1 month of starting the medication, and it reverses within a month of discontinuing the medication. Monitoring the sodium level in the elderly for at least 1 month when commencing an SSRI is suggested.

Although SSRIs do not have the cardiac arrhythmia risk associated with TCAs, arrhythmia risk is especially pertinent in overdose, and suicide risk must always be considered, especially when treating a child or adolescent with mood disorder. A small number of case reports, such as those by King et al^[99] and Teicher et al,^[100] have described a putative association between SSRI administration and increased suicidality (perhaps linked to behavioral activation or akathisia). However, although such phenomena may have occurred in a small number of cases, several studies suggest that SSRIs, like other antidepressants, generally reduce the risk of suicide in adult patients who are depressed.

A large-scale study that followed >80,000 women ages 54-79 for 6 years found that women who suffer depression and use antidepressants face an increased risk of stroke. The risk of stroke multiplied 1.29 times in women with a history of depression, compared to those who reported they were never diagnosed with the condition.^[101]

Abrupt discontinuation of SSRIs with shorter half-lives, such as paroxetine, may induce withdrawal symptoms, some of which may mimic a relapse or recurrence of a depressive episode (eg, tiredness, irritability, severe somatic symptoms). The withdrawal symptoms can appear after as few as 6-8 weeks of SSRI treatment. For clinical practice and education, the FDA has recommended that physicians who prescribe these medications should closely monitor patients with observation that "would generally include at least weekly face-to-face contact during the first 4 weeks of treatment" with specific visit intervals specified after those 4 weeks.

Awareness of possible interactions with other medications is important. To varying degrees, the SSRIs inhibit the metabolism of several medications that are metabolized by the diverse clusters of hepatic cytochrome P450 isoenzymes (eg, TCAs, neuroleptics, antiarrhythmics, benzodiazepines, carbamazepine, theophylline, warfarin, terfenadine [removed from United States market]).

In addition, interactions of SSRIs with other serotonergic medications, particularly MAOIs, may induce the serotonergic syndrome, marked by agitation, confusion, and hyperthermia. SSRIs also have a high rate of protein binding, which can lead to increased therapeutic or toxic effects of other protein-bound medications. MAOIs should not be administered less than 5 weeks after discontinuation of fluoxetine and less than 2 weeks for other SSRIs. Also, the clinician should not prescribe SSRIs within 2 weeks after stopping the MAOIs.

Bupropion is associated with a risk of seizure at higher doses, especially in patients with a history of seizure or epileptic disorders. Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2-, and histamine (H1) receptors and, thus, can be very sedating. Adverse effects such as drowsiness and weight gain may tend to improve over time and with higher doses. Trazodone is very sedating and usually is used as a sleep aid rather than as an antidepressant.

Nelson et al demonstrated that discontinuance of therapy because of adverse events was higher for atypical antipsychotics than for placebo and that adjunctive atypical antipsychotics were significantly more effective than placebo.^[102] The researchers conducted a large meta-analysis to determine the efficacy and tolerability of adjunctive atypical antipsychotic agents in major depressive disorder by pooling data from 16 trials (acute-phase, parallel-group, double-blind, randomized controlled) representing 3480 patients. The authors concluded that atypical antipsychotic agents effectively augment therapy in major depressive disorder, but they are associated with an increased risk for adverse effects.^[102]

The adverse effects of TCAs largely are due to their anticholinergic and antihistaminic properties, and these include sedation, confusion, dry mouth, orthostasis, constipation, urinary retention, sexual dysfunction, and weight gain. Caution should be used in patients with cardiac conduction abnormalities.

Consultation can be important at many stages of the treatment process. Certainly, consultation should be sought if the treating physicians exhaust the options with which they feel comfortable.

A psychiatrist must be involved in the care of patients in whom more severe symptoms develop and for whom a more intensive level of care will be needed (eg, suicidal ideation, psychosis, mania, severe decline in physical health). Expertise in pharmacotherapy, other somatic therapies, and psychotherapy should be readily available. Collaboration of psychiatrists and family practitioners/internists is of particular importance in patients with acute and chronic medical issues. A psychologist can be involved if psychologic testing or more intensive specialized psychotherapy (eg, interpersonal therapy, cognitive-behavioral therapy) is needed.

With the patient's consent, communication with the patient's therapist can be invaluable in guiding medical treatment of major depressive disorder. The therapist can provide information regarding clinical progress, symptoms, and adverse effects. This can facilitate timely and appropriate medical interventions.

Observe patients at least monthly, depending on their clinical status, functioning, support systems, environmental stressors, motivation for treatment, and the presence of comorbid psychiatric or other medical disorders. Medications should be reevaluated for drug-drug or drug-disease state interactions at every visit, as well as reevaluated for efficacy every 8-12 weeks. Nonresponse to treatment should raise the possibility of alternative diagnoses (eg, bipolar or dementia).

Monitoring mood and treatment response can be done during the clinical interview with use of the screening tools mentioned earlier (see Clinical Presentation) and, in pediatric or elderly patients, with collateral interviews with the family or caregiver. The 2011 APA guideline supports the use of rating scale tools for evaluating the ongoing success of the treatment plan.^[62] The patient’s functional status and ability to perform activities of daily living should be evaluated at every visit. Suicidal ideation should be evaluated at each visit and between visits when indicated.

Psychotherapy can be used not only to consolidate the skills learned during the acute phase of treatment and help patients cope with the psychosocial sequelae of the depression but also to address the antecedents, contextual factors, environmental stressors, and intrapsychic conflicts that may contribute to a relapse. If the patient is taking antidepressants, psychotherapy can be used to foster medication compliance. In adolescents, one study suggested that monthly cognitive-behavioral therapy sessions may be effective to prevent relapses of depression.^[103]