Treatment of depression with atypical features: a meta-analytic approach

The present meta-analysis addressed the empirical evidence regarding the treatment of major depression with atypical features. The superiority of monoamine oxidase inhibitors (MAOIs) compared with other antidepressants in the treatment of major depression with atypical features has been frequently reported. According to the CONSORT Statement, studies included in our meta-analysis had to meet several criteria, especially a double-blind, controlled condition and an operational diagnosis according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-III or DSM-IV criteria, respectively. Four databases for research-based evidence were used in a systematic review: Medline, Embase, Psyndex and PsycInfo. Only eight publications met inclusion/exclusion criteria, resulting in 11 comparisons. Our results contrast an effect size of 0.45 (95% confidence interval) for a comparison of MAOIs vs. placebo with an effect size of 0.02 (95% confidence interval: - 0.10-0.14) for a comparison of MAOIs vs. selective serotonin reuptake inhibitors. The effect size for MAOIs vs. tricyclic antidepressants was 0.27 (95% confidence interval: 0.16-0.42). MAOIs may be more effective for atypical major depressive disorder than tricyclic antidepressants. Most clinical research has been conducted on irreversible MAOIs. Additional studies testing more recently developed antidepressants (including reversible MAOIs) with an improved safety profile would be warranted. The available data are insufficient for a direct comparison between MAOIs and selective serotonin reuptake inhibitors.     

Widespread hypothalamic–pituitary–adrenocortical axis‐relevant and mood‐relevant effects of chronic fluoxetine treatment on glucocorticoid receptor gene expression in mice

Tricyclic antidepressants (TCAs) have been used to treat melancholic depression, which has been associated with elevated hypothalamic–pituitary–adrenocortical (HPA) axis activity, whereas patients suffering from atypical depression, which is often associated with decreased HPA axis activity, show preferential responsiveness to monoamine oxidase inhibitors (MAOIs). We previously reported drug‐specific effects of the TCA imipramine and the MAOI phenelzine on HPA axis‐relevant endpoints in mice that may explain differential antidepressant responses in melancholic vs. atypical depression. However, selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in both melancholic and atypical depression. We therefore hypothesized that SSRIs would share HPA axis‐related effects with either TCAs or MAOIs. To test this hypothesis, we measured HPA axis‐relevant gene expression in male C57BL/6 mice treated for 5 weeks with 10 mg/kg/day fluoxetine. To control for potential fluoxetine‐induced changes in glucocorticoid secretion, mice were adrenalectomized and given fixed levels of glucocorticoids. Fluoxetine decreased glucocorticoid receptor (GR) gene expression in the prefrontal cortex, amygdala, locus coeruleus and dorsal raphé nucleus, and increased locus coeruleus tyrosine hydroxylase and dorsal raphé nucleus tryptophan hydroxylase‐2 (TPH2) gene expression. These results resembled those that we previously reported for MAOI treatment, but included decreases in GR and increases in TPH2 gene expression in the dorsal raphé nucleus that were induced by TCAs but not MAOIs. Correlating with inhibitory effects on central amygdala GR gene expression, fluoxetine also decreased amygdala corticotropin‐releasing hormone gene expression, an effect not previously observed with MAOIs or TCAs. These actions may be relevant to the efficacy of SSRIs in treating a range of depression and anxiety disorders.     

The role of monoamine oxidase inhibitors in depression treatment guidelines

Monoamine oxidase inhibitors (MAOIs) have proven efficacy for treating depression and for decades have been a preferred treatment for patients with atypical depression, high levels of anxiety, anergic bipolar depression, and treatment-resistant depression. However, MAOIs are infrequently used due to safety and tolerability concerns and the need for dietary restrictions. Current guidelines, which are reviewed here, recommend MAOIs as third-, fourth-, or fifth-line treatments due to these concerns. However, a transdermal formulation of selegiline limits the need for dietary restrictions and has fewer side effects than many more widely used antidepressants. The availability of a safer and more tolerable formulation gives clinicians another option in their armamentarium for treating depression.     

Treating depression with atypical features

Depression with atypical features was first recognized in a subset of patients with depression who preferentially responded to the monoamine oxidase inhibitor (MAOI) phenelzine, in contrast to patients with melancholic depression. This article reviews the history of approaches in treating depression with atypical features. Initial studies in the early 1980s focused on phenelzine, but an unfavorable adverse effect profile limits its clinical use. Despite such difficulties, phenelzine remains the gold standard in eliciting high response rates in nearly two thirds of patients with atypical depression. Searches for agents with improved safety profiles led to studies of tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), chromium, and cognitive therapy approaches. Of these, TCAs showed inferior efficacy to MAOIs but also had cumbersome adverse effects. SSRIs have reported efficacy, but a lack of direct comparative studies limits clinical decision making. Cognitive strategies have shown promise, but demonstrating efficacy in comparison with an MAOI and placebo is limited to a single study. Despite advances in agents for melancholic depression, treatment for atypical depression remains dependent upon older agents for the greatest efficacy.     

MAOIs and depression treatment guidelines

Monoamine oxidase inhibitors (MAOIs) have proven efficacy for treating depression, particularly in patients with atypical depression, high levels of anxiety, anergic bipolar depression, and treatment-resistant depression. However, MAOIs are not supported as first-line treatments due to safety and tolerability concerns and the need for dietary restrictions; instead, current guidelines recommend MAOIs as third-, fourth-, or fifth-line treatments. However, a newer, transdermal MAOI formulation limits the need for dietary restrictions and has fewer sexual and metabolic effects than some of the newer antidepressants.     

The transdermal delivery system of monoamine oxidase inhibitors

Monoamine oxidase inhibitors (MAOIs) were once widely used as effective treatments for major depressive disorder, particularly for patients with atypical or treatment-resistant depression. Today, MAOIs have largely been replaced by newer antidepressants because of concerns over potential serious side effects due to their mechanism of action. Monoamine oxidase (MAO) is an enzyme that metabolizes serotonin, norepinephrine, and dopamine, the neurotransmitters that are most associated with depression; inhibiting MAO, therefore, makes more of these neurotransmitters available for synaptic action. However, MAO also metabolizes tyramine, a trace amine found in some foods that acts as a sympathomimetic. Allowing excess tyramine to accumulate via MAO inhibition can result in hypertensive crisis due to the release of norepinephrine; therefore, patients taking an MAOI have had to follow dietary restrictions to avoid tyramine-rich foods. Hypertensive crisis may also be precipitated by using MAOIs in conjunction with other drugs that have vasoconstrictive properties, that act as sympathomimetics, or that inhibit the reuptake of norepinephrine. Serotonin syndrome is another serious adverse effect that can potentially occur when using an MAOI with another drug that inhibits the reuptake of serotonin. In this article, the mechanism of action of MAOIs is reviewed, along with that of a newer MAOI formulation that lessens the need for dietary restrictions and has a greater safety and tolerability profile than the older oral formulations.     

Treating DSM-IV depression with atypical features

Depression with atypical features is characterized by mood reactivity and 2 or more symptoms of vegetative reversal (including overeating, oversleeping, severe fatigue or leaden paralysis, and a history of rejection sensitivity). Another important feature of atypical depression is its preferential response to monoamine oxidase inhibitor (MAOI) treatment, especially phenelzine, relative to tricyclic antidepressants (TCAs). The efficacy of newer agents relative to MAOIs and TCAs is unclear. This presentation reviews currently available treatments for DSM-IV depression with atypical features, focusing specifically on placebo-controlled trials. Although phenelzine shows the most efficacy in this population, treatment with TCAs, selective serotonin reuptake inhibitors, cognitive-behavioral therapy, MAOIs other than phenelzine, and other agents are discussed. Following this presentation is a discussion on the treatment of depression with atypical features by experts in this subject area.     

The noradrenergic action in antidepressant treatments: pharmacological and clinical aspects

Even though noradrenaline has been recognized as one of the key neurotransmitters in the pathophysiology of major depression (MD), noradrenergic compounds have been less extensively utilized in clinical practice, compared to selective serotonin reuptake inhibitors (SSRIs). The development of the first selective noradrenergic reuptake inhibitor (NRI), Reboxetine, has not substantially changed the state of the art. In addition, Atomoxetine, a relatively pure NRI used for the treatment of ADHD, has shown mixed results when administered in augmentation to depressed subjects. Through a Medline search from 2000 to 2010, the present article provides an updated overview of the main pharmacological and clinical aspects of antidepressant classes that, partially or selectively, act on the noradrenergic systems. The noradrenergic action plays an important clinical effect in different antidepressant classes, as confirmed by the efficacy of dual action antidepressants such as the serotonin noradrenaline reuptake inhibitors (SNRIs), the noradrenergic and dopaminergic reuptake inhibitor (NDRI) Bupropion, and other compounds (e.g., Mianserin, Mirtazapine), which enhance the noradrenergic transmission. In addition, many tricyclics, such as Desipramine and Nortriptyline, have prevalent noradrenergic effect. Monoamine oxidase inhibitors (MAOIs), moreover, block the breakdown of serotonin, noradrenaline, dopamine and increase the availability of these monoamines. A novel class of antidepressants--the triple reuptake inhibitors--is under development to selectively act on serotonin, noradrenaline, and dopamine. Finally, the antidepressant effect of the atypical antipsychotic Quetiapine, indicated for the treatment of bipolar depression, is likely to be related to the noradrenergic action of its metabolite Norquetiapine. Even though a pure noradrenergic action might not be sufficient to obtain a full antidepressant effect, a pronoradrenergic action represents an important element for increasing the efficacy of mixed action antidepressants. In particular, the noradrenergic action seemed to be related to the motor activity, attention, and arousal.     

The use of monoamine oxidase inhibitors in primary care

Although primary care clinicians have developed considerable expertise in managing patients with major depressive disorder, and a range of treatment strategies is currently available, some patients still fail to reach remission. Two strategies have fallen out of common use: treating patients with monoamine oxidase inhibitors (MAOIs) and subgrouping patients by diagnosis when selecting antidepressant treatment. Monoamine oxidase inhibitors became less popular because other treatments were perceived to be safer and easier to use. However, a newer transdermal formulation of an MAOI that limits the need for the dietary restrictions of oral MAOIs may make it worthwhile to consider using this class of medication in patients who have failed several treatment trials. Although adverse events due to patients' diets are less likely with the transdermal MAOI, clinicians should still be alert for drug interactions and observe recommended washout periods. Patients who may benefit from MAOI treatment include those with treatment-resistant depression, atypical depression, anxiety, or anergic bipolar depression and those who have experienced intolerable metabolic or sexual side effects with other medications.     

Enhancing central noradrenergic function in depression: is there still a place for a new antidepressant?

Noradrenaline has long played a key role in the way the etiology of depression is conceptualized and in the mechanism of action of many current antidepressants. Tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), selective noradrenaline reuptake inhibitors (NRIs), the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine, and many atypicals, like mianserin and bupropion, influence, at least in part, central noradrenergic function. Enhancement of noradrenergic function may be particularly helpful in patients with melancholia. However, while noradrenaline will continue to be a target for research into the etiology and treatment of depression, it is unlikely that antidepressants acting solely on noradrenaline will be pursued.     

Treatment of social phobia with antidepressants

This article reviews evidence for the utility of antidepressant medications in the treatment of social phobia. Monoamine oxidase inhibitors (MAOIs) were the first antidepressants shown to be effective for social phobia, but dietary restrictions and a relatively high rate of adverse effects often relegate MAOIs to use after other treatments have been found ineffective. Reversible inhibitors of monoamine oxidase (RIMAs) hold promise as safer alternatives to MAOIs, but RIMAs may be less effective and are currently unavailable in the United States. Selective serotonin reuptake inhibitors (SSRIs), of which paroxetine has been the best studied in social phobia to date, have recently emerged as a first-line treatment for the generalized subtype of social phobia. The SSRIs are well tolerated and consistently have been shown to be efficacious in controlled trials.     

The use of MAOIs in primary care

Once a mainstay of antidepressant treatment, monoamine oxidase inhibitors (MAOIs) have largely been abandoned in favor of medications with improved safety profiles. However, remission rates for patients with depression remain low, and primary care physicians continue to have patients who either do not respond or only partially respond to newer medications. MAOIs have proven efficacy for depression, particularly for patients with atypical depression, high levels of anxiety, anergic bipolar depression, and treatment-resistant depression. A transdermal delivery system has been developed for an MAOI that avoids the need for patients to follow dietary restrictions and has fewer metabolic and sexual side effects than some newer medications, which may make it particularly suited for use in primary care.     

Refractory depression treated with high doses of monoamine oxidase inhibitor

Two treatment-refractory cases of depression were treated with doses of monoamine oxidase inhibitors (MAOIs) that exceeded the recommended therapeutic range. Both patients improved without any side effects. It appears that high doses of MAOIs when used with caution in responsible patients may be another method for treating refractory depression.     

Pharmacotherapy for late-life depression

The 2001 expert consensus guidelines for treating major depressive disorder (MDD) in geriatric patients recommended antidepressant treatment in combination with psychotherapy. Recent evidence continues to support the use of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors as first-line agents in the elderly, and although the transdermal monoamine oxidase inhibitor selegilene has shown promise in adult patients, it has not been studied in geriatric depression. Augmentation therapy with atypical antipsychotics or other agents may provide benefits for agitated, psychotic, or resistant MDD in the elderly. The few treatment studies that have been conducted in the geriatric population since the publication of the guidelines have had mixed results and high placebo response rates. More large controlled trials are needed.     

Translating the evidence on atypical depression into clinical practice

Although the introduction of selective serotonin reuptake inhibitors ushered in an era of relative comfort among clinicians in treating major depressive disorder (MDD), no one antidepressant is appropriate for all patients with depression. In patients with atypical symptoms, efficacy of therapeutic agents may be greatest for monoamine oxidase inhibitors (MAOIs). The first-generation MAOIs such as phenelzine and isocarboxazid were largely nonselective inhibitors of both subtypes of MAO, MAO(A) and MAO(B). These medications carried with them dietary restrictions, medication restrictions, a need for titration, and a substantial side effect burden, including weight gain, cardiovascular effects (i.e., hypertension and hypotension), and sexual side effects. The second-generation MAOI selegiline is selective for MAO(B) at oral doses of up to 10 mg/day. At higher doses, selegiline loses selectivity and inhibits both MAO(A) and MAO(B). Because the antidepressant effects of selegiline occur with the higher doses that impact tyramine pressor effects, an ideal formulation would optimize dose while minimizing adverse effects of MAO(A) inhibition in the gastrointestinal mucosa. Efforts in this direction led to formulation of the selegiline transdermal system (STS). The most common side effects are irritation at the patch site and insomnia. Drugs to be avoided with the STS include some pain medications, antidepressants, muscle relaxants, and any form of sympathomimetic amines, which include amphetamines, cold products with pseudoephedrine, phenylephrine, phenylpropanolamine, ephedrine, and stimulant-containing weight-reduction agents. Although no tyramine-restricted diet is required for the 6-mg/24-hour patch, a restricted diet is recommended for the higher-dose patches to reduce the risk of hypertensive crisis.     

Atypical depression: retrospective self‐reporting of treatment effectiveness

Objective: Earlier studies demonstrated that those with atypical depression show a differentially superior response to monoamine oxidase inhibitor (MAOI) antidepressants. This study compares ratings of effectiveness for a range of treatments, amongst depressed subjects with and without atypical features. Method: In an on‐line survey, individuals experiencing likely clinical depression rated symptoms experienced when depressed, including ‘atypical features’ and the effectiveness of previous treatments. Mean treatment effectiveness ratings were compared amongst those with ‘atypical depression’ (n = 338) and ‘non‐atypical depression’ (n = 377). Results: There were few significant differences between the ‘atypical depression’ and ‘non‐atypical depression’ groups in effectiveness ratings for drug treatments, and none for psychological treatments. The ‘atypical depression’ group had significantly lower mean effectiveness ratings for some selective serotonin reuptake inhibitor antidepressants. Few respondents had trialed MAOIs. Conclusion: While MAOIs are rarely prescribed, a range of non‐MAOI drug and psychological treatments are of some perceived benefit for depressed patients with atypical features.     

Forms of atypical depression and their response to antidepressant drugs

Three definitions of atypical depression are evaluated with respect to the effects of monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs) on the basis of pooled data from several double-blind studies. Those three definitions of atypical depression are depression with associated panic, depression secondary to a diagnosis of anxiety, and depression with reversed vegetative change. In none of these forms was a drug difference observed. However, when gender was taken into account, MAOIs were superior to TCAs in depressed women with panic attacks, whereas TCAs were superior to MAOIs in depressed men with panic attacks.     

Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update

Monoamine oxidase inhibitors (MAOIs) are effective treatments for depression that has atypical features or that has failed to respond to other antidepressants. However, MAOIs are underused because clinicians are concerned about dietary and drug interactions with this class of medication. Hypertensive crisis and serotonin syndrome can occur in rare cases due to interactions between MAOIs and foods containing tyramine as well as interactions with serotonergic and sympathomimetic agents. A better understanding of the foods and drugs that can cause adverse reactions, as well as knowledge of newer MAOIs with mechanisms of action and delivery methods that reduce these risks, may help clinicians to consider the use of these medications, when appropriate, in their patients with depression.     

The effectiveness of atypical antipsychotic medications in depressive disorders

Clinical evidence supporting the use of atypical antipsychotic medication (broad-spectrum psychotropic agents) in the treatment of depressive disorders is increasing rapidly. Animal models suggest that when atypical antipsychotic medications are used in combination with a selective serotonin reuptake inhibitor there is additional activation of frontal dopaminergic and noradrenergic neurotransmitter systems. This stimulated the initiation of several clinical trials that showed the efficacy of atypical antipsychotic medication augmentation of selective serotonin reuptake inhibitors for patients with treatment-resistant depression. There also are few case reports of successful treatment of depression with atypical antipsychotic medication alone. When a clinician is treating a depressed patient who did not achieve relief after trials with two different antidepressant regimens, one option to consider is augmentation with an atypical antipsychotic medication to ameliorate depressive symptoms.     

Issues in adherence to treatment with monoamine oxidase inhibitors and the rate of treatment failure

In 2000, the economic burden of depression in the United States was estimated to be $83.1 billion. Although many effective treatments are available and treatment rates have increased, response and remission rates for patients with depression remain low and multiple treatment trials are often required. Whether patients are adherent to their medication affects response and remission rates, and nonadherence is common among patients with depression. Increasing adherence improves treatment outcomes and lowers treatment costs. Interventions that increase adherence include educational, behavioral, affective, and provider-targeted strategies; transdermal delivery of drugs also may increase adherence by simplifying the patient's medication regimen. While monoamine oxidase inhibitors (MAOIs) have proven efficacy for depression, particularly for patients with treatment-resistant or atypical depression, they are underprescribed due, in part, to concerns over dietary and drug restrictions that are required to avoid potential serious side effects. However, newer MAOI formulations, including a transdermal delivery system, have improved safety and tolerability profiles and avoid or lessen the need for dietary restrictions, giving clinicians another option for treating patients who may be nonadherent or nonresponsive to their current antidepressant.