Pharmacologic Therapy for Depression
Drugs used for treatment of depression include the following:
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin/norepinephrine reuptake inhibitors (SNRIs)
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
St. John’s wort
Selective serotonin reuptake inhibitors
SSRIs include the following:
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 they are also the first-line medications for late-onset depression. This recommendation is supported by the 2011 APA guideline.
The adverse-effect profile of SSRIs is less prominent than that of some other agents, which promotes better compliance. Common adverse effects include gastrointestinal upset, sexual dysfunction, and changes in energy level (ie, fatigue, restlessness).
The SSRIs are thought to be relatively unproblematic in patients with cardiac disease, as these agents do not appear to affect blood pressure, heart rate, cardiac conduction, or cardiac rhythm. However, dose-dependent QT prolongation has been reported with citalopram.
Consequently, the US Food and Drug Administration (FDA) has advised that citalopram is not recommended in patients with congenital long QT syndrome.Use of citalopram may be appropriate for patients with this condition who lack viable alternatives; however, in such cases, the drug should be given at a low dose, and electrocardiographic and/or electrolyte monitoring should be performed. Citalopram should be discontinued in patients who are found to have a persistent corrected QT interval (QTc) greater than 500 ms.
The dose of citalopram should not exceed 40 mg/day, because of the risk of potentially fatal cardiac arrhythmias; furthermore, higher doses have not been shown to be more effective in treating depression. For patients older than 60 years, the maximum recommended dose of citalopram is 20 mg/day.[91, 92]
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 as second-line agents in patients who have not responded to SSRIs.
The concurrent use of SNRIs with other antidepressants may be more problematic. For example, the Combining Medications to Enhance Depression Outcomes (CO-MED) study found that the combination of extended-release venlafaxine plus mirtazapine may actually pose a greater risk of adverse events and does not outperform monotherapy.
The safety, tolerability, and side-effect profiles of SNRIs include those of the SSRIs, as well as noradrenergic side effects, such as hypertension.
Atypical antidepressants include bupropion (Wellbutrin), mirtazapine (Remeron), nefazodone, and trazodone (Desyrel). They have all been found to be effective in monotherapy in major depressive disorder and may be used in combination therapy for more difficult to treat depression.
Nevertheless, this group also shows low toxicity in overdose. In addition, bupropion has the advantage over the SSRIs of causing less sexual dysfunction and less GI distress. Mirtazapine is associated with a high risk of weight gain, so patients who are treated with this agent should have careful monitoring of weight.
TCAs include the following:
TCAs have a long record of efficacy in the treatment of depression. They are used less commonly because of their side-effect profile and their considerable toxicity in overdose (see AntidepressantToxicity).
Monoamine oxidase inhibitors
MAOIs include isocarboxazid (Marplan), phenelzine (Nardil), selegiline (Emsam), and tranylcypromine (Parnate). These agents are widely effective in a broad range of affective and anxiety disorders. 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
St. John’s wort (Hypericum perforatum) is an herbal remedy available over the counter. Although St. John’s wort is considered a first-line antidepressant in many European countries, it has only recently gained popularity in the United States. Uses include treatment of mild to moderate depressive symptoms, but of note, it has not been shown to be effective in major depressive episodes and cannot be recommended as a first-line treatment in moderate depression.
St. John’s wort may act as an SSRI. The common 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 recommended.
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.
Comparative effectiveness of antidepressants
The AHRQ found that average effectiveness of those 12 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.
Zisook et al found that among depressed patients with suicidal ideation at baseline, the combination of sustained-release bupropion and escitalopram was more effective at reducing suicidal ideation than sustained-release venlafaxine plus mirtazapine; the former was most effective at week 12 of treatment. In this study, of 665 outpatients with nonpsychotic chronic and/or recurrent major depressive disorder, 4 patients attempted suicide; all were receiving venlafaxine plus mirtazapine.
Antidepressant effectiveness and depression severity
In a meta-analysis, Fournier et al found that medication superiority over placebo increased with increases in baseline depression severity, crossing the threshold for a clinically significant difference at a baseline Hamilton Depression Rating Scale (HDRS) score of 25. In patients with mild or moderate depression, antidepressant medication had minimal or no benefit compared with placebo, but in patients with very severe depression, antidepressant drugs provided a substantial benefit compared with placebo.
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, BLT has the potential to precipitate a hypomanic or 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.
In addition to its established role in seasonal affective disorder, BLT may be effective in nonseasonal depression or as an augmenting agent with antidepressant medication. Studies have demonstrated benefit of BLT for treatment of nonseasonal depression in pregnant patients and elderly patients.[101, 102]
Additional Therapies for Depression
Transcranial magnetic stimulation (TMS) has been approved by the FDA for the treatment of major depressive disorder when one class of antidepressant has failed. A double-blind, multicenter, controlled TMS trial found that 30.4% of patients in the trial’s active treatment group achieved remission from major depression after 5 weeks of TMS treatment.
The study included 233 patients, all of whom suffered from major depression and had previously failed to respond to therapeutic treatments or could not tolerate antidepressant medication because of side effects. The TMS device used in the trial received FDA approval in 2013 for the treatment of depression.
Vagus nerve stimulation (VNS) has been approved by the FDA for use in adult patients who have failed to respond to at least 4 adequate medication and/or ECT treatment regimens. The device requires surgical implantation.
A meta-analysis of the therapeutic effect of physical exercise in depressed individuals revealed a short-term (≤16 wk) small positive effect on depression scores, but no long-term benefit was shown. 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 physical exercise as an “antidepressant.”
Deep brain stimulation (DBS) appears to be a safe and effective long-term treatment for treatment-resistant depression. Experience with this invasive technique is limited, however, and the method remains experimental.
In one third to two thirds of cases of depression, patients fail to remit with first-line therapy.[106, 94] No factors have been identified for reliably predicting whether an individual patient will respond.
Assessment of patients with treatment-resistant depression should include consideration of the following:
Accuracy of diagnosis and possible comorbid medical conditions
Adequacy of medication dose and duration of treatment, as well as adherence to treatment regimen
Possible comorbid psychiatric conditions (eg, substance abuse, anxiety disorders, 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 :
Increasing the medication dose to the maximum tolerated
Augmenting the current medication with another antidepressant
Changing to a different antidepressant
Adding psychotherapy or more intensive care if not already completed
Considering the use of ECT
The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the largest open-label trial to date, examined various strategies for treatment-resistant depression. The STAR*D trial showed that in patients who did not respond to an initial SSRI (citalopram), switching to another SSRI antidepressant, changing medication class, and switching to CBT were all equally effective treatments. Achieving remission, rather than partial response, was the best predictor of a better long-term prognosis.[106, 107]
The AHRQ found conflicting evidence regarding the differences between second-generation antidepressants for treatment-resistant depression. A good-quality study revealed no substantial differences in the effectiveness of sustained-release bupropion, sertraline, and sustained-release venlafaxine; however, fair-quality studies indicated a trend toward greater effectiveness with venlafaxine than with citalopram, fluoxetine, or paroxetine.
Augmentation combinations can include the following:
Bright-light therapy plus any antidepressant
Buspirone (BuSpar) plus a TCA or SSRI
Lithium (Eskalith, Lithane, Lithobid) plus any antidepressant
Methylphenidate (Ritalin) or dextroamphetamine (Dexedrine) plus any antidepressant other than an MAOI
TCA plus an SSRI
Triiodothyronine (Cytomel) plus any antidepressant
The STAR*D trial found that augmentation of an SSRI with bupropion and augmentation with buspirone were equally effective after a lack of response to the SSRI.
Aripiprazole (Abilify) is the first drug approved by the FDA for adjunctive treatment in major depressive disorder and the first drug to receive FDA approval for use in treatment-resistant depression.[108, 109, 110]
Increasingly, pediatric patients with depression have been treated with SSRIs or CBT. Fluoxetine is the only medication currently approved by the FDA for the treatment of depression in children. There are few studies on the use of medications for pediatric patients with major depressive disorder, and some of those that have been performed have methodologic problems. Additionally, very few pharmacokinetic studies have been performed in children, and most of those have focused on the effects of TCAs. In adolescents, suicidality associated with antidepressants is an important issue.
The clinician needs to inform parents and patients about adverse effects, dose, timing of therapeutic effect, and 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.
The Texas Children’s Medication Algorithm Project has created a consensus guideline for the treatment of major depression in pediatric patients that is based on evidence from scientific studies and the clinical expertise of the panel, which included child and adolescent psychiatry clinicians and research experts. The guideline is as follows:
For mild depression, CBT or interpersonal psychotherapy is recommended first
For pharmacologic therapy, SSRIs are the first-line choice
If there is no response to the SSRI, switch to a second SSRI
In the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study, patients who did not respond to an initial SSRI and were switched to combination therapy with CBT plus either another SSRI or venlafaxine had no better response than switching medications alone. However, a switch to any second medication provided a good response, and each of the medications provided a similar response.
Selective serotonin reuptake inhibitors
The use of SSRIs as first-line medications in pediatric patients is supported by reports that these agents are effective in this population and have a relatively safe adverse-effect profile and very low lethality after overdose; in addition, SSRIs offer the convenience of once-daily administration. Several studies have reported a 70-90% response rate to SSRIs in adolescents with major depressive disorder.[114, 115, 116]
Children and adolescents with major depressive disorder responded significantly more frequently to fluoxetine (58%) than to placebo (32%), according to Emslie et al in an 8-week double-blind study. 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 regimens 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 SSRI treatment increases the number of pediatric patients with late improvement is not clear. The Treatment of Adolescents with Depression Study (TADS) demonstrated significant increases in response to treatment over time (see Table 1, below).
Table 1. Treatment Response Over Time in the Treatment of Adolescents with Depression Study (Open Table in a new window)
|Treatment||Response Rate (%)|
|Week 12||Week 18||Week 36|
|Cognitive-behavioral therapy (CBT)||48||65||81|
|Fluoxetine plus CBT||73||85||86|
In TADS, suicidal ideation decreased less with fluoxetine therapy than with combination therapy or CBT. Suicidal events, but not actual suicides, occurred more often in patients receiving fluoxetine therapy (14.7%) than combination therapy (8.4%) or CBT (6.3%).
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 may help clarify concerns about toxicity or 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.
In December 2003, the UKMedicinesandHealthcareProductsRegulatoryAgency(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.
A systematic review and meta-analysis by Tsapakis et al of randomized controlled trials of antidepressant therapy in young people with depression concluded that antidepressants of all types showed limited efficacy in juvenile depression. However, these researchers found that fluoxetine might be more effective, especially in adolescents.
Antidepressants and suicidality in youths
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 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 should be placed on all antidepressants, indicating that they increase the risk of suicidal thinking and behavior (suicidality)
A patient information sheet (“Medication Guide”) should be provided to the patient and the patient’s caregiver with every prescription
The results of controlled pediatric trials of depression should be included in the labeling for antidepressant drugs
The Psychopharmacologic Drugs and Pediatric Advisory Committees recommended that the products not be contraindicated, because access was important for those who could benefit from them. For more information, see theFDAStatementonRecommendations of thePsychopharmacologicDrugsandPediatric AdvisoryCommittees.
Given the possibility of increased suicidality, the FDA recommended that physicians who prescribe antidepressants to pediatric patients provide close monitoring in these cases. Close monitoring includes at least weekly face-to-face contact with patients or their family members or caregivers during the first 4 weeks of treatment; visits every other week for the next 4 weeks; visit at 12 weeks; and then visits as clinically indicated beyond 12 weeks. Additional contact by telephone may be appropriate between office visits.
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 and an increase in suicidality. It has also been noted that monitoring of these patients did not increase following the warnings.[119, 120]
Antidepressants were associated with a significant reduction in the risk of suicidal behavior in observational study by Leon et al, which followed 757 patients over a 27-year period. This study included participants with psychiatric and other medical comorbidity and those receiving acute or maintenance therapy, polypharmacy, or no psychopharmacologic treatment at all. The results suggest, however, that 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.[122, 123, 124] The Treatment for Adolescents with Depression Study (TADS) lends support for fluoxetine’s efficacy in adolescent depression, notably the combined use of fluoxetine and CBT. Data from the TADS study also suggested a possible protective effect of CBT against suicidality when used in combination with fluoxetine.
Additionally, a study by the Group Health Cooperative in Seattle of more than 65,000 children and adults treated for depression found that suicide risk declines, not rises, with the use of antidepressants. This is the largest study to date to address this issue. This study also showed that with psychotherapy and antidepressant drug therapy, the highest risk of suicide was in the month prior to seeking treatment. The month following initiation of treatment was also a period of high risk for both types of treatment, emphasizing the importance of close follow-up after treatment initiation.
TCAs are no longer considered the first-line treatment for pediatric patients with depressive disorders; however, individual cases may respond better to TCAs than to other medications. TCAs may also be useful for those with comorbid attention deficit hyperactivity disorder (ADHD), enuresis, and narcolepsy, as well as for augmentation strategies.
The TCAs require a baseline electrocardiogram (ECG), resting blood pressure, and pulse rate. 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. Plasma levels should be monitored to measure compliance and to avoid toxicity. In addition, weight should 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.
Depression During Pregnancy
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. One meta-analysis found that the possible risks of untreated peripartum depression include increased risk of preterm birth, low birth weight, slower head growth, and intrauterine growth restriction. There is no clear evidence that available antidepressants are teratogenic.
APA guidelines support psychotherapy as the first choice of therapy for pregnant women with mild depression. In severe depression during pregnancy, especially in cases of psychosis, agitation, or severe retardation, electroconvulsive therapy may be the safest and quickest treatment option. One randomized, double-blind study found that bright-white-light therapy was significantly more effective than placebo for depression during pregnancy.
Conflicting evidence exists regarding the use of SSRIs during pregnancy and an increased risk of persistent pulmonary hypertension of the newborn (PPHN). An initial Public Health Advisory in 2006 was based on a single retrospective study. Since then, studies have yielded conflicting findings, with 3 trials suggesting risk and 3 trials finding no risk of PPHN associated with antidepressants.[128, 129]
In a December 2011 review, the FDA 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 advises 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.
A further possible risk for infants born to women taking SSRIs is neonatal withdrawal symptoms, which includes high-pitched crying, tremors, and disturbed sleep. In one study, 30% of neonates exposed to SSRIs in utero developed withdrawal symptoms, typically peaking within 2 days of birth but sometimes as long as 4 days after birth. These investigators recommended monitoring exposed neonates for as long as 48 hours after birth.
Principles of treatment of 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.
A Cochrane review of 28 trials involving approximately 17,000 women concluded that psychosocial and psychological interventions can significantly reduce the number of women who develop postpartum depression. Women who received interventions including intensive, individualized postpartum home visits by nurses and midwives; peer-based telephone support; and interpersonal psychotherapy had an average risk ratio of 0.78, compared with women who received standard care.
Patients with postpartum depression 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 breast-feeding; however, this has not been studied thoroughly, and the same risk-benefit considerations should be applied as when treating depression during pregnancy.
Postpartum blues are typically mild and resolve spontaneously; no specific treatment is required, other than support and reassurance. For first episodes of depression in postpartum women, 6-12 months of treatment is recommended. For women with recurrent major depression following pregnancy, long-term maintenance treatment with an antidepressant is indicated.
Antidepressants and Breast-feeding
Most antidepressants probably can be used safely during breast-feeding; however, this has not been studied thoroughly, and the same risk-benefit considerations should be applied as when treating depression during pregnancy.
Women who plan to breast-feed must be informed that antidepressants, like all psychotropic medications, are secreted into breast milk. Concentrations in breast milk vary widely. Data on the use of TCAs, fluoxetine (Prozac), sertraline (Zoloft), and paroxetine (Paxil) during breast-feeding are encouraging, and serum antidepressant levels in the breast-fed infant are either low or undetectable. Reports of toxicity in breast-fed infants are rare, although the long-term effects of exposure to trace amounts of medication are not known.
Antidepressants and the Elderly
Geriatric psychopharmacology follows the tenet of “start low, go slow, but go.” This is based on the 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 from drug-drug or drug-disease interactions.
Most classes of medications have been associated with an increased risk of falls 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.
Start antidepressant medications at a lower dose (often, 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, 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 be used in the elderly only 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. Often, the nausea is short-lived, but when it is not, further options should be evaluated.
The value of pharmacologic treatment of refractory depression in geriatric patients remains uncertain. Cooper et al reviewed 14 studies of the management of depressive episodes that failed to respond to at least one course of treatment in patients aged 55 years and older. They found that half of the patients responded to further pharmacologic treatments; however, they noted that most of the studies had significant methodologic problems and that none were double-blind, randomized, placebo-controlled trials.
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:
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
Diet and Activity
Dietary restrictions are necessary only when prescribing monoamine oxidase inhibitors (MAOIs). Foods high in tyramine, which can produce a hypertensive crisis in the presence of MAOIs, should be avoided. These foods include the following:
Aged chicken or beef liver
Air-dried sausage and similar meats
Beer and wine (in particular, red wine)
Pickled or cured meat or fish
Physical activity and exercise contribute to recovery from major depressive disorder. Patients should be counseled regarding stress reduction.
Complications of Treatment for Depression
Clinically significant hyponatremia may develop in elderly patients taking SSRIs. In addition to older age, risk factors include the following :
Low body weight
Respiratory or CNS illnesses
Previous episodes of hyponatremia
Concomitant use of other medications (particularly diuretics)
Antidepressant-induced hyponatremia occurs 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 after starting the medication, and it reverses within a month after discontinuing the medication. Monitoring the sodium level in the elderly for at least 1 month after commencing an SSRI is suggested.
Although SSRIs do not have the same risk of cardiac arrhythmia as is present with TCAs, arrhythmia risk is especially pertinent in overdose. In addition, 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 and Teicher et al, 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 more than 80,000 women aged 54-79 found that women who suffer depression and use antidepressants face an increased risk of stroke. The hazard ratio for stroke was 1.29 for women with a history of depression. A systematic review and meta-analysis of prospective studies found a hazard ratio of 1.45 for total stroke and 1.55 for fatal stroke.
Abrupt discontinuation of SSRIs that have shorter half-lives, such as paroxetine, may induce withdrawal symptoms, some of which may mimic a 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. In addition to causing rebound depression, paroxetine discontinuation can also cause cholinergic rebound. Moreover, relapse may occur earlier after rapid withdrawal (< 15 days) than after more gradual withdrawal (≥ 15 days).
Interactions with other drugs
Awareness of possible interactions with other medications is important. To varying degrees, but especially for fluvoxamine, the SSRIs inhibit the metabolism of several medications that are metabolized by the diverse clusters of hepatic cytochrome P-450 isoenzymes (eg, TCAs, neuroleptics, antiarrhythmics, benzodiazepines, carbamazepine, theophylline, warfarin, terfenadine [removed from United States market]). This inhibition results in higher plasma levels of those agents.
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 after discontinuation of other SSRIs. Also, the clinician should not prescribe SSRIs within 2 weeks after stopping the MAOIs.
The adverse effects of TCAs, which result largely from their anticholinergic and antihistaminic properties, include the following:
Caution should be used in patients with cardiac conduction abnormalities.
Bupropion is associated with a risk of seizure at doses above 450 mg a day, especially in patients with a history of seizure or epileptic disorders. This risk appears much lower in the sustained-release bupropion preparations.
Mirtazapine is a potent antagonist at 5-HT2, 5-HT3, alpha2-, and histamine (H1) receptors and, thus, can be very sedating and frequently causes weight gain. Adverse effects such as drowsiness may tend to improve over time and with higher doses. Trazodone is very sedating and usually is used as a sleep aid in small doses (ie, 25 to 50 mg) rather than as an antidepressant.
Nelson et al demonstrated that although adjunctive atypical antipsychotics (bupropion, mirtazapine, trazodone) were significantly more effective than placebo for augmenting therapy in major depressive disorder, discontinuance of therapy because of adverse events was higher for atypical antipsychotics than for placebo.
Consultation can be important at many stages of the treatment process. Certainly, treating physicians should seek consultation if they 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 psychological testing or more intensive specialized psychotherapy (eg, interpersonal therapy, cognitive-behavioral therapy) is needed.
Structured care in which nonmedical specialists augment primary care may offer an improved model. The use of an allied health professional supervised by a psychiatrist integrated into the primary care treatment of depression has been shown to double rates of adherence to antidepressants and significantly improve response to depression treatment.
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. Patient factors influencing the follow-up schedule include the following:
Motivation for treatment
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 or alternative treatment.
Monitoring of mood and treatment response can be done during the clinical interview with use of the screening tools mentioned earlier (see 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 such as the PHQ-9 for evaluating the ongoing success of the treatment plan.
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.
Drugs used for the treatment of depression include the following:
Selective serotonin reuptake inhibitors (SSRIs)
Serotonin/norepinephrine reuptake inhibitors (SNRIs)
Tricyclic antidepressants (TCAs)
Monoamine oxidase inhibitors (MAOIs)
St. John’s wort (Hypericum perforatum)
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 treatme
SSRIs are the initial antidepressants of choice for uncomplicated depression because of their minimal anticholinergic effects.
They 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.
The SSRIs are not thought to be 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.[91, 92]
Because the adverse-effect profile of SSRIs is less prominent than other agents, improved compliance is promoted. Common adverse effects of SSRIs include gastrointestinal upset, sexual dysfunction, bleeding, emotional blunting, cognitive dysfunction, and changes in energy level (ie, fatigue, restlessness).
The US Food and Drug Administration issued a safety information update in December 2011 concluding that it is unclear whether the use of SSRIs during pregnancy causes persistent pulmonary hypertension in the newborn. The FDA currently recommends that health care professionals and patients weigh the small potential risk of persistent pulmonary hypertension against the substantial risks of untreated depression during pregnancy.
Citalopram enhances serotonin activity as a result of selective reuptake inhibition at the presynaptic neuronal membrane. It has minimal effects on norepinephrine and dopamine.
Although it has FDA approval only for depression, citalopram is commonly prescribed for other psychiatric disorders, including obsessive-compulsive disorder, generalized anxiety disorder, panic disorder, and premenstrual dysphoric disorder.
The FDA advises that the dose of citalopram not exceed 40 mg/day because of the risk of potentially fatal QT prolongation. Furthermore, higher doses have not been shown to be more effective in treating depression.
Escitalopram is an SSRI and S-enantiomer of citalopram used for the treatment of depression. The mechanism of action is thought to be potentiation of serotonergic activity in the central nervous system resulting from inhibition of CNS neuronal reuptake of serotonin. Escitalopram has little or no effect on norepinephrine and dopamine reuptake.
Onset of depression relief may occur after 1-2 wk, but individual responses vary, and a full effect may not be seen until 8-12 weeks.
Fluoxetine is a commonly used SSRI and was the first of the SSRIs to become available in the United States. It selectively inhibits presynaptic serotonin reuptake with minimal or no effect on reuptake of norepinephrine or dopamine. It is commonly prescribed for many indications that are not FDA approved, including fibromyalgia, posttraumatic stress disorder, Raynaud phenomenon, social anxiety disorder, and selective mutism.
Fluvoxamine enhances serotonin activity due to selective reuptake inhibition at the neuronal membrane. It does not significantly bind to alpha-adrenergic, histamine, or cholinergic receptors and thus has fewer side effects than tricyclic antidepressants. Fluvoxamine is a strong inhibitor of cytochrome P-450. Although fluvoxamine is FDA approved only for obsessive-compulsive disorder, it is commonly prescribed for other psychiatric disorders, including social anxiety disorder, posttraumatic stress disorder, pain disorder, and major depression.
Paroxetine is a potent selective inhibitor of neuronal serotonin reuptake and also has a weak effect on norepinephrine and dopamine neuronal reuptake. It has slight anticholinergic effects and may cause more weight gain than other SSRIs. Paroxetine is sometimes prescribed for indications that are not FDA approved, such as eating disorders and the relief of vasomotor symptoms of menopause.
Sertraline selectively inhibits presynaptic serotonin reuptake. It has very minimal effects on norepinephrine and dopamine neuronal uptake. Sertraline is sometimes prescribed for indications that are not FDA approved, such as eating disorders, generalized anxiety disorder, and panic disorder.
Vilazodone’s mechanism of antidepressant effect is related to serotonergic activity in the CNS through selective inhibition of serotonin reuptake. This agent is also a partial agonist at serotonergic 5-HT1A receptors, although the contribution of this activity to the drug’s antidepressant effect is unknown.
Vilazodone is indicated for major depressive disorder. The dose should be adjusted when this agent is given with moderate or strong CYP3A4 inhibitors.
nts. Often, treatment failures are caused not by clinical resistance but by medication noncompliance, inadequate duration of therapy, or inadequate dosing.
Antidepressants can have central and peripheral anticholinergic effects, as well as sedative effects, and can block the active reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine. SSRIs are metabolized via the cytochrome P-450 system and may have drug interactions on that basis. The degree of enzyme inhibition varies among SSRIs. Effects on blood levels and bioavailability of coadministered drugs, as well as pharmacodynamic interactions, account for most clinically significant SSRI-drug interactions.
All available antidepressants appear to work via one or more of the following mechanisms :
Presynaptic inhibition of uptake of 5-HT or NE
Antagonist activity at presynaptic inhibitory 5-HT or NE receptor sites, thereby enhancing neurotransmitter release
Antagonism of NE beta or serotonin 5-HT2 receptors
N-Methyl-D-aspartate (NMDA) receptor antagonism
Induction of brain-derived neurotrophic factor (BDNF)
Inhibition of monoamine oxidase, thereby reducing neurotransmitter breakdown
SNRIs can be used as first-line agents, particularly in patients with significant fatigue or pain syndromes associated with the episode of depression. The SNRIs also have an important role as second-line agents in patients who have not responded to SSRIs. Safety, tolerability, and side-effect profiles are similar to those of the SSRIs, with the exception that venlafaxine and desvenlafaxine have been associated (rarely) with a sustained rise in blood pressure. Venlafaxine has been particularly associated with hyponatremia.
Desvenlafaxine is an SNRI that is indicated for the treatment of major depressive disorder.
Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine uptake, and antidepressant action is thought to be due to serotonergic and noradrenergic potentiation in the central nervous system.
Venlafaxine and its active metabolite inhibit neuronal serotonin and norepinephrine reuptake. They are weak inhibitors of dopamine reuptake. In addition, it causes beta-receptor down-regulation. Venlafaxine is sometimes prescribed for non–FDA-approved indications, such as obsessive-compulsive disorder, hot flashes, neuropathic pain, attention-deficit/hyperactivity disorder, and posttraumatic stress disorder.
TCAs have a long record of efficacy in the treatment of depression and have the advantage of lower cost. They are used less commonly because of the need to titrate the dose to a therapeutic level and because of their considerable toxicity in overdose. TCAs are often prescribed for many other psychiatric disorders, such as generalized anxiety disorder and posttraumatic stress disorder. They are also used to treat chronic pain, such as neuropathy, and migraine headaches.
Amitriptyline inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane, which increases concentration in the CNS. It has a high affinity for histamine H1 and muscarinic M1 receptors. Amitriptyline can cause weight gain, sedation, and anticholinergic side effects. It is often used for non–FDA-approved indications, such as chronic pain management, diabetic neuropathy, migraine prophylaxis, and posttraumatic stress disorder.
Desipramine inhibits the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It is a commonly used TCA that is relatively less sedating and tends to have fewer anticholinergic and antihistaminic adverse effects than other TCAs. It is sometimes used for off-label indications such as peripheral neuropathy and attention-deficit/hyperactivity disorder.
Imipramine is one of the oldest agents available for the treatment of depression. It is demethylated in the liver to desipramine. Imipramine inhibits the reuptake of norepinephrine and, more potently, serotonin at the presynaptic neuronal membrane. It has a strong affinity for alpha-adrenergic, H1, and M1 receptors. Common side effects include orthostasis, sedation, weight gain, and anticholinergic effects. It is also used off-label in the treatment of panic disorder, posttraumatic stress disorder, and attention deficit/hyperactivity disorder.
Clomipramine potently inhibits the reuptake of serotonin at the presynaptic neuronal membrane. It has strong affinities to both H1 and M1 receptors, which results in sedation, weight gain, and anticholinergic side effects. Although clomipramine is FDA approved only for obsessive-compulsive disorder, it has also been prescribed for depression, panic attacks, and chronic pain.
Nortriptyline blocks the reuptake of serotonin and, more potently, norepinephrine at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than other TCAs. Although nortriptyline is FDA approved only for depression, it has also been prescribed for chronic pain, myofascial pain, anxiety disorders, and attention-deficit/hyperactivity disorder. As with desipramine, there is a therapeutic window for nortriptyline
Protriptyline increases the synaptic concentration of norepinephrine in the CNS by inhibiting reuptake at the presynaptic neuronal membrane. It has less affinity for H1 and M1 receptors and, thus, is better tolerated than tertiary amine TCAs.
Doxepin increases the concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These effects are associated with a decrease in the symptoms of depression. It has the highest affinity for H1 receptors of all TCAs and, thus, is very sedating and can cause weight gain.
Trimipramine inhibits reuptake of norepinephrine and serotonin at the presynaptic neuron and elicits strong anticholinergic effects. It has a high affinity for the H1 receptor and is thus very sedating, but it is useful for gastroesophageal reflux.
Amoxapine inhibits reuptake of norepinephrine and, to a lesser extent, serotonin at the presynaptic neuron. It also blocks dopamine receptors, causing it to have antipsychotic activity, as well.
Atypical antidepressants include bupropion (Wellbutrin, Wellbutrin SR), mirtazapine (Remeron), and trazodone (Desyrel). These agents are effective in treating major depression and may be effective in combination therapy in major depressive disorder. This group also shows low toxicity in overdose. Wellbutrin SR may have an advantage over the SSRIs by causing less sexual dysfunction and weight gain.
Bupropion inhibits neuronal dopamine reuptake and decreases the rate of norepinephrine activity. In addition to major depressive disorder, the indications for bupropion include smoking cessation. Off-label indications include attention-deficit/hyperactivity disorder and depression associated with bipolar disorder. Common side effects include headache and mild weight loss. Unlike other antidepressants, bupropion does not cause sexual dysfunction.
Mirtazapine blocks both presynaptic and postsynaptic alpha-2 receptors but has low affinity for alpha-1 receptors. It also blocks serotonin receptors 5HT2 and 5HT3. Common side effects include sedation, weight gain, and dry mouth.
Trazodone is effective in the treatment of major depression. It inhibits reuptake of serotonin and modulates serotonergic neurotransmission. It also significantly blocks histamine (H1) receptors. Its most common side effect is sedation, and thus, it has an off-label indication as a hypnotic. It can be very rarely associated with priapism, a medical emergency and a dangerous side effect of this drug in men. It is often used at a low dosage (25 to 50 mg) as an adjunct to SSRIs to treat insomnia.
Augmentation is a common strategy for treatment-resistant depression. It consists of adding a medication with a different mechanism of action to the therapeutic regimen.
Lithium carbonate can be used as an effective augmenting agent in combination with an antidepressant in cases of treatment-resistant depression. It can also be used to treat or prevent episodes of depression. Lithium is contraindicated in patients with significant renal impairment.
It is important to note that lithium interacts with many drugs. Use of lithium often requires monitoring of lithium levels and renal and thyroid function tests.
Buspirone is marketed as an antianxiety medication; however, it may have antidepressant effects at doses above 45 mg/day. The antidepressant effects may increase when buspirone is used in combination with SSRIs and TCAs in patients with treatment-resistant depression. Buspirone is a partial 5-HT1A agonist with serotonergic and some dopaminergic effects in the CNS. It has anxiolytic effects but may take up to 2-3 weeks for full efficacy.
The CNS stimulants dextroamphetamine (Dexedrine) and methylphenidate (Ritalin) are sometimes used to augment antidepressants in patients with resistant depression.
This is an augmenting agent in resistant depression. It has been studied most for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.
Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.
Methylphenidate has been mostly studied for treating patients who are medically ill and depressed. It is available as a sustained-release preparation.
Thyroid hormones liothyronine (T3, Cytomel) may modulate the effect of antidepressants.
This synthetic salt of endogenous thyroid hormone may convert nonresponders (ie, nonresponders to antidepressants) to responders by increasing receptor sensitivity and enhancing the effects of TCAs.
Neurology & Psychiatry, Herbals
Although St. John’s wort is considered a first-line antidepressant in many European countries, it has only recently gained popularity in the United States. Uses include treatment of mild to moderate depressive symptoms, but efficacy has not been demonstrated for major depression.
St John’s wort is believed to act as an antidepressant by increasing concentrations of CNS neurotransmitters, including serotonin. The common 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.