Neurovegetative Features Research Articles

Appetite Changes in Depression are Associated With Salience Neurocircuitry

Increasing evidence suggests that neurovegetative features of Major Depressive Disorder (MDD), specifically appetite changes, are associated with specific immunometabolic and neurobiological profiles. Although MDD in general has been associated with aberrant resting-state functional connectivity, it remains to be elucidated whether neurovegetative symptoms are associated with distinct neural connectivity patterns.

Cytokine secretion and the risk of depression development in patients with connective tissue diseases

Research in the past two decades has revolutionized our understanding of depressive illnesses. Proinflammatory cytokines have become a point of interest in the interconnecting areas of neuropsychiatric and autoimmune diseases. The cytokine hypothesis of depression suggests that pro-inflammatory cytokines play a primary role in the mediation of the pathophysiological characteristics of major depression, in which an inflammatory process may be induced by external and internal stressors, such as psychological and inflammatory diseases, respectively. The higher prevalence of depression, particularly in patients with chronic autoimmune connective tissue disorders (CTD), suggests that depression may present a dysfunctional adaptation of cytokine-induced sickness, which could manifest in times of an exacerbated activation of the innate immune system. Inflammation is thought to contribute to the development of clinical depression through its ability to induce sickness behaviors corresponding to the neurovegetative features of depression, through the dysregulation of the hypothalamic-pituitary-adrenal axis, alterations in neurotransmitter synthesis and reuptake, and through its involvement in the neuroprogression pathways. This review explores the complex interrelationships in which inflammatory responses alter neuroendocrine and neuropsychological regulation contributing to depressive symptoms in CTD. The prevalence and characteristics of depression, and its correlation to the levels of inflammatory cytokines and disease activity among different CTD will be reviewed.

Melancholia: Past and Present

To investigate commonalities in the clinical presentation of melancholia over time. I conducted a comparative study to 2 epidemiologically complete databases from 1875-1924 and 1995-2005. Patients in the historical period (1875-1924, compared with 1995-2005) with a diagnosis of melancholia show a classic profile of endogenous onset, with remission after 6 months, neurovegetative features, and, commonly, psychosis. The incidence of psychotic presentations appears to have fallen in recent decades. Patients in the contemporary period (1995-2010, compared with 1875-1924) at first admission for severe depressive disorders are more likely at an older age, more likely to go on to die by suicide, and will have much more frequent admissions. The data from this study support classical perceptions of melancholia. The poor outcomes in contemporary cases of severe depressive disorders support arguments for distinguishing between melancholia and other depressive disorders.

Central administration of murine interferon-α induces depressive-like behavioral, brain cytokine and neurochemical alterations in mice: A mini-review and original experiments

A role for pro-inflammatory cytokines and their neuroinflammatory signaling cascades in depressive pathology has increasingly gained acceptance. In this regard, several lines of evidence suggested that interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) can provoke neurochemical and hormonal changes akin to those associated with psychological stressors, and that these cytokines also induce sickness behaviors that resemble some of the neurovegetative features of depression. Similarly, human depressed patients often display marked changes of pro-inflammatory cytokine levels and immune cell activity. Perhaps more germane in the analysis of the cytokine-depression connection, reports of humans undergoing interferon-α (IFN-α) treatment for certain cancers or viral infections have indicated that the pro-inflammatory cytokine caused signs of major depression in a substantial subset of those treated. In the present investigation, we demonstrated that acute or repeated infusion of IFN-α into the lateral ventricles provoked depressive-like behavior and concomitant changes in serotonin (5-HT) and mRNA expression of particular 5-HT receptors and pro-inflammatory cytokines. These actions were less evident following administration directly into the prefrontal cortex and not apparent at all when administered to the dorsal raphe nucleus. The data are discussed in relation to the induction of depression elicited by IFN-α, and are presented in the context of a mini-review that highlights potential mechanisms through which the cytokine might act to promote psychomotor and affective disturbances and interact with stressors.

Guidelines for youth depression: time to incorporate new perspectives

TO THE EDITOR: I cannot argue with the push by Hickie and McGorry for services for young people from 12 to 25 years of age who suffer from “depression”. But I question their sequencing of treatments model that pervades the beyondblue draft clinical practice guidelines about which they editorialise. Their model presupposes a unitary entity of “major depression” that varies in severity, with milder conditions being treated by psychotherapy and more severe conditions being treated with antidepressant medication. Consider the following case to show how the guidelines get it wrong. A 16-year-old girl presents with her first episode of moderately severe major depression. She is treated as per the guidelines for depression with a selective serotonin reuptake inhibitor (SSRI) and rapidly develops a severe psychotic mania. She is certified to a psychiatric facility and requires a prolonged admission. For the next 2 years she remains chronically hypomanic, refusing to try better treatment. Eventually, following a severe depressive episode, her treatment is reorganised and her condition stabilises. However, the trauma and psychosocial damage from the hospitalisation and prolonged period of illness are significant. In the guidelines, bipolar disorder — arguably the only “biological” kind of depression in this age group — is separated from the body of recommendations for managing depression. The possibility that this episode of depression may be part of an asyet-undeclared bipolar disorder needs to be thoroughly integrated into the understanding and management of “depression”. Features that would suggest possible bipolar disorder include psychomotor retardation and cognitive impairment, psychosis, reverse neurovegetative features (hypersomnia or hyperphagia), a few manic symptoms mixed with depression (racing thoughts, distractibility, flight of ideas, increased energy or psychomotor agitation), or the depression not making sense psychologically. Past episodes of depression, brief hypomania, anti-depressant-induced hypomania, or a family history of bipolar disorder also need to be documented. Doctors should then routinely discuss with patients and families the possibility that bipolar disorder could be diagnosed, and warn that the patient may experience a manic switch. If the likelihood is high, as part of a proper process of informed consent, the patient should be offered concurrent lithium or antipsychotic medication. The patient and family can be assured that expert clinical observation over time will clarify the diagnosis and what treatment is appropriate. This approach not only involves the patient and family in decision making, giving knowledge and choices, but, importantly, incorporates the reality of diagnostic uncertainty.

Guidelines for youth depression: time to incorporate new perspectives

TO THE EDITOR: I cannot argue with the push by Hickie and McGorry for services for young people from 12 to 25 years of age who suffer from “depression”. But I question their sequencing of treatments model that pervades the beyondblue draft clinical practice guidelines about which they editorialise. Their model presupposes a unitary entity of “major depression” that varies in severity, with milder conditions being treated by psychotherapy and more severe conditions being treated with antidepressant medication. Consider the following case to show how the guidelines get it wrong. A 16-year-old girl presents with her first episode of moderately severe major depression. She is treated as per the guidelines for depression with a selective serotonin reuptake inhibitor (SSRI) and rapidly develops a severe psychotic mania. She is certified to a psychiatric facility and requires a prolonged admission. For the next 2 years she remains chronically hypomanic, refusing to try better treatment. Eventually, following a severe depressive episode, her treatment is reorganised and her condition stabilises. However, the trauma and psychosocial damage from the hospitalisation and prolonged period of illness are significant. In the guidelines, bipolar disorder — arguably the only “biological” kind of depression in this age group — is separated from the body of recommendations for managing depression. The possibility that this episode of depression may be part of an asyet-undeclared bipolar disorder needs to be thoroughly integrated into the understanding and management of “depression”. Features that would suggest possible bipolar disorder include psychomotor retardation and cognitive impairment, psychosis, reverse neurovegetative features (hypersomnia or hyperphagia), a few manic symptoms mixed with depression (racing thoughts, distractibility, flight of ideas, increased energy or psychomotor agitation), or the depression not making sense psychologically. Past episodes of depression, brief hypomania, anti-depressant-induced hypomania, or a family history of bipolar disorder also need to be documented. Doctors should then routinely discuss with patients and families the possibility that bipolar disorder could be diagnosed, and warn that the patient may experience a manic switch. If the likelihood is high, as part of a proper process of informed consent, the patient should be offered concurrent lithium or antipsychotic medication. The patient and family can be assured that expert clinical observation over time will clarify the diagnosis and what treatment is appropriate. This approach not only involves the patient and family in decision making, giving knowledge and choices, but, importantly, incorporates the reality of diagnostic uncertainty.

Stability of symptoms across major depressive episodes in bipolar disorder

Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated. We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression. A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes. While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.

P02-21 Depression and cytokines: A psychoneuroimmune perspective

Background:Cytokine-induced sickness behaviour is an adaptative response to infection. Activation of the immune system, particularly the increased activity of several cytokines, has been implicated in the provocation or exacerbation of mood disorders.Aim:To discuss the relevance of psychoneuroimmunologic research in the understanding of the patophysiology and therapeutic targets of certain mental health disorders.Methods:Review of the literature. MEDLINE and PubMed databases searches for peer-reviewed studies, published between 2000 and 2008, using combinations of the Medline Subject Heading terms cytokines, sickness behaviour, immune system and depression, depressive illness.Results:Several lines of evidence support the relationship between cytokines and mood disorders. Cytokine elevations are more marked in severe depression and their activity may also relate with illness chronicity, neurovegetative features and high stress perception. It is argued that the activation of the inflammatory system, eliciting cytokine release and synthesis, provoke neuroendocrine and neurotransmitter changes, contributing to the development of depression. Some studies support that the brain cytokine system can become sensitized in response to non-immune stressors or to immune stressors occurring early in life.Discussion:The cytokines actions in the brain can help to clarify the patophysiology of certain psychiatric disorders, including depression. The research findings show an association between the activation of the brain cytokine system and depression, although the precise relationship between sickness behaviour and depression is still not clear. Further research in such a promising area of study is needed and can contribute to new therapeutical targets and a broader understanding of psychiatric disorders.

PW06-02 Depression and cytokines: A psychoneuroimmune perspective

Background:Cytokine-induced sickness behaviour is an adaptative response to infection. Activation of the immune system, particularly the increased activity of several cytokines, has been implicated in the provocation or exacerbation of mood disorders.Aim:To discuss the relevance of psychoneuroimmunologic research in the understanding of the patophysiology and therapeutic targets of certain mental health disorders.Methods:Review of the literature. MEDLINE and PubMed databases searches for peer-reviewed studies, published between 2000 and 2008, using combinations of the Medline Subject Heading terms cytokines, sickness behaviour, immune system and depression, depressive illness.Results:Several lines of evidence support the relationship between cytokines and mood disorders. Cytokine elevations are more marked in severe depression and their activity may also relate with illness chronicity, neurovegetative features and high stress perception. It is argued that the activation of the inflammatory system, eliciting cytokine release and synthesis, provoke neuroendocrine and neurotransmitter changes, contributing to the development of depression. Some studies support that the brain cytokine system can become sensitized in response to non-immune stressors or to immune stressors occurring early in life.Discussion:The cytokines actions in the brain can help to clarify the patophysiology of certain psychiatric disorders, including depression. The research findings show an association between the activation of the brain cytokine system and depression, although the precise relationship between sickness behaviour and depression is still not clear. Further research in such a promising area of study is needed and can contribute to new therapeutical targets and a broader understanding of psychiatric disorders.

Depressive Symptoms and Metabolic Syndrome: Is Inflammation the Underlying Link?

Behavioral alterations, including depression, are frequent in individuals with the metabolic syndrome (MetS). Recent findings suggest that chronic activation of innate immunity might be involved. The objective of this study was to examine the relationship between MetS and depressive symptoms and to elucidate the involvement of inflammation in this relationship. Participants were 323 male twins, with and without MetS and free of symptomatic cardiovascular disease, drawn from the Vietnam Era Twin Registry. Depressive symptoms were measured with the Beck Depression Inventory (BDI). Inflammatory status was assessed using C-reactive protein (CRP) and interleukin-6 (IL-6); twins with both CRP and IL-6 levels above the median were classified as having an elevated inflammatory status. Factor analysis was performed on individual BDI items to extract specific symptom dimensions (neurovegetative, mood, affective-cognitive). Subjects with MetS had more depressive symptoms than those without. Depressive symptoms with neurovegetative features were more common and more robustly associated with MetS. Both the BDI total score and each symptom subscore were associated with inflammatory biomarkers. After adjusting for age, education, and smoking status, the MetS was significantly associated with the BDI total score and the neurovegetative score. After further adjusting for inflammation, the coefficient for MetS decreased somewhat but remained statistically significant for the BDI neurovegetative subscore. When controlling for the MetS, inflammation remained significantly associated with the BDI mood subscore. The MetS is associated with higher depressive symptomatology characterized primarily by neurovegetative features. Inflammation is one determinant of depressive symptoms in individuals with MetS.

Atypical Major Depression - Past, Present, and Future

The term “Atypical Depression” refers to a subtype of mood disorder that has been most clearly associated with reversed neurovegetative features and interpersonal deficits such as rejection sensitivity and social avoidance. The most robust clinical correlates of atypical depression include a high preponderance of female cases, an early age of onset, and high rates of chronicity and co-morbidity. Particularly strong links to early adversity and chronic stress have also been described. Regarding treatment outcomes, atypical depression has historically been associated with both MAOI responsiveness and tricyclic resistance, with recent data further suggesting that it is the early onset atypical subgroup that accounts for these findings. There have been few large scale studies of newer anti-depressants such as SSRIs and buproprion in atypical depression, although practical issues have encouraged the use of these agents as first-line treatments. Going forward, high priorities for research include optimizing the definition of atypical depression for DSM-V, more clinical studies with newer anti-depressant classes, and a greater focus on developmentally-based research that considers intergenerational transmission of risk, gene-environment interaction and adverse early environments. Keywords: Atypical major depression, depressive subtyping, epidemiology, pathophysiology, treatment response, developmental strategies, early onset, chronicity

Bipolar depression: Diagnostic and treatment considerations

Bipolar affective disorder is a recurrent, disabling, and potentially lethal illness that typically begins early in life. Although the disorder is defined by the manic and hypomanic episodes, for most people the depression episodes are the more virulent aspect of the illness. Specifically, the depressive episodes are more numerous, last longer, and are more difficult to treat than the manias, and depression is the principal cause of the illness's increased mortality due to suicide. For people with early-onset depression, predictors of subsequent bipolarity include a family history, psychotic features, and reverse neurovegetative features. Initial episodes of depression are commonly misdiagnosed, which often delays initiation of appropriate therapy and increases the likelihood of treatment with antidepressants alone. Unfortunately, the correct diagnosis is often not made until there has been a treatment-emergent affective switch. There are no treatments specifically approved for bipolar disorder in youth and, among antidepressants, only fluoxetine has received approved. When bipolarity is suspected, treatment with mood stabilizers, both conventional (i.e., lithium, valproate, and carbamazapine) and more recently classified (lamotrigine) and atypical antipsychotics should be prioritized. When antidepressants are indicated in combination with mood stabilizers, first choice options include bupropion and the selective serotonin reuptake inhibitors. Studies of adults indicate that several forms of focused psychotherapy may improve longer term outcomes.

Bipolar Depression: Issues in Diagnosis and Treatment

Although bipolar affective disorder is defined by the history of manic or hypomanic episodes, depression is arguably a more important facet of the illness. Depressive episodes, on average, are more numerous and last longer than manic or hypomanic episodes, and most suicides occur during these periods. Misdiagnosis of major depressive disorder delays initiation of appropriate therapy, further worsening prognosis. Distinguishing features of bipolar depression include earlier age of onset, a family history of bipolar disorder, presence of psychotic or reverse neurovegetative features, and antidepressant-induced switching. Bipolar I depressions should initially be treated with a mood stabilizer (carbamazapine, divalproex, lamotrigine, lithium, or an atypical antipsychotic); antidepressant monotherapy is contraindicated. More severe or "breakthrough" episodes often require a concomitant antidepressant, such as bupropion or a selective serotonin reuptake inhibitor (SSRI). The first treatment specifically approved for bipolar depression is a combination of the SSRI fluoxetine and the atypical antipsychotic olanzapine. For refractory depressive episodes, venlafaxine, the monoamine oxidase inhibitor tranylcypromine, and ECT are most widely recommended. The optimal duration of maintenance antidepressant therapy has not been established empirically and, until better evidence-based guidelines are established, should be determined on a case-by-case basis.

Update on the Biology of Seasonal Affective Disorder

The etiology and pathophysiology of seasonal affective disorder (SAD) has been linked to the seasons and to light since its first conceptualization. Aspects of SAD that make it particularly amenable to biological investigation include the predictable recurrent episodes, the rapid response to a nonpharmacologic treatment, the specific neurovegetative features, and the availability of rich animal models of seasonality. This paper reviews new findings for the major biological hypotheses for SAD, focusing on circadian rhythms, neurotransmitters, and molecular genetics. Integrative issues and future directions for the study of SAD, including the heuristic value of a dual-vulnerability hypothesis that conceptualizes seasonality as a dimensional construct and the importance of studying endophenotypes, will be discussed.

Cytokines, stress, and depressive illness

It has been suggested that immune activation, and particularly increased activity of several cytokines, notably interleukin-1, interleukin-2, interleukin-6, tumor necrosis factor-α as well as their soluble receptors is characteristic of depression. Normalization of cytokine activity does not necessarily occur following successful antidepressant, suggesting that cytokines may be trait markers of depression, or simply represent bystander effects of the illness. The relationship between cytokines and depression is complicated as a variety factors could directly or indirectly influence cytokine activity. While cytokine elevations are most pronounced in severe (melancholic) depression, their activity may also be related to chronicity of illness, neurovegetative features of depression (altered sleep patterns, food intake, weight changes, fatigue or general activity), or the high stress perception characteristic of depression. Although, studies assessing cytokines in depressive populations are basically correlational in nature, patients receiving cytokine immunotherapy frequently show depressive symptoms, which may be attenuated by antidepressant medication, supporting a causal role for cytokines in depressive disorders. The processes underlying such outcomes remain to be established, but the affective changes may stem from the neuroendocrine and central neurochemical changes elicited by cytokines, as these are reminiscent of those associated thought to subserve depression.

Lymphocyte proliferation among major depressive and dysthymic patients with typical or atypical features

Background: Depressive illness may be associated with immune and cytokine alterations. However, data are unavailable concerning functional immune changes associated with chronic, low-grade depression (dysthymia). Moreover, the contribution of the neurovegetative features of depression (e.g., altered sleep, eating) to the immune alterations remains to be determined. Methods: Mitogen-stimulated cell proliferation was assessed in major depressive and dysthymic patients exhibiting either typical or atypical features. In a subset of patients, lymphocyte proliferation was also assessed before and after pharmacotherapy to determine whether alleviation of symptoms would be accompanied by normalization of immune functioning. Results: Lymphocyte proliferation was reduced to a greater extent among dysthymic than among major depressive patients. Among dysthymic patients reduced cell proliferation was evident irrespective of symptom typicality; however, among major depressive patients the contribution of neurovegetative features varied with the specific mitogen used. Symptom alleviation following antidepressant treatment was not accompanied by normalization of cell proliferation. Limitations: Patients received 12 weeks of antidepressant treatment, and more sustained therapy may be required for normalization of immune activity. As well, conclusions concerning normalization of immune functioning in drug-treated major depressive patients requires that a greater number of patients be assessed. Conclusions: As the immune variations were more pronounced in dysthymia than in major depression, chronicity of illness may be a pertinent factor in promoting immune disturbances. This does not exclude the possibility that depression is associated with immune activation, which then provokes suppression of other aspects of immunity. As well, it is conceivable that immune alterations indirectly contribute to the symptoms accompanying depressive state, although it does not appear that variations of lymphocyte proliferation are associated with neurovegetative status.

Symptoms predicting inpatient service use among patients with bipolar affective disorder.

Symptoms that were risk factors for hospital readmission among psychiatric inpatients diagnosed as having bipolar affective disorder were evaluated. Subjects were 100 persons consecutively admitted to a psychiatric inpatient unit at a university-affiliated hospital who met Research Diagnostic Criteria for bipolar I or II disorder or schizoaffective disorder, manic type. Patients were assessed using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) and the Brief Psychiatric Rating Scale (BPRS) within one week of discharge, and their hospitalization status was documented by monthly phone contacts over a period of 15 months. Twenty-four patients (24 percent) were rehospitalized within six months of discharge, and 44 (44 percent) were readmitted within 15 months. Survival analysis using the Cox proportional hazard regression model demonstrated that patients with high scores on a BPRS-derived mania factor were at significantly decreased risk of rehospitalization, whereas those scoring high on a factor consistent with neurovegetative depression were at significantly increased risk. A greater number of previous psychiatric admissions and younger age were also associated with significantly increased risk of rehospitalization. The findings suggest that patients with bipolar disorder presenting with a depressive episode characterized by prominent neurovegetative features should be treated more aggressively with both pharmacotherapy and intensive outpatient services to reduce the relatively high risk of rehospitalization that appears to be associated with this type of depression.

Neurological correlates of depressive symptoms in Alzheimer's disease and vascular dementia

Background. Organic brain disease such as dementia or stroke is associated with depression. In dementia, depressive symptoms are common where there is evidence of vascular disease and in Alzheimer's disease they often coexist with extrapyramidal signs. Method. In a study of 60 patients with Alzheimer's disease and 39 patients with vascular dementia, depressive symptoms were rated using the Cornell Scale for Depression in Dementia. Neurological signs were assessed and severity of cognitive impairment was measured with the Mini-Mental State Examination. Results. Depressive symptoms were more severe in vascular dementia. Pyramidal tract signs had no relationship to depression in either type of dementia. In vascular dementia, extrapyramidal and grasp reflexes were strongly related to the severity of depression, and were associated with neurovegetative features. In Alzheimer's disease, extrapyramidal signs were the strongest independent predictor of the severity of depression. Conclusion. Depressive symptoms are more severe in vascular dementia compared to Alzheimer's disease and were related to neurological abnormalities.

Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features.

Depression has been associated with both suppression and enhancement of various aspects of immune functioning. It was of interest to determine whether cytokine alterations associated with depression, including interleukin-1 (IL-1beta) and interleukin-2 (IL-2), were related to the neurovegetative symptom profile or to the chronicity of the illness. Circulating ACTH, cortisol, norepinephrine (NE) and epinephrine levels, and production of IL-1beta and IL-2 from mitogen-stimulated lymphocytes were assessed in classical major depression, atypical depression (ie, with reversed neurovegetative features), and dysthymia (chronic depression without comorbid major depression) with either typical or atypical profiles, as well as nondepressed control subjects. Among atypical depressives, plasma ACTH levels were elevated while cortisol was reduced relative to controls. Irrespective of neurovegetative profile, IL-1beta production was increased in dysthymic patients, and was highly correlated with age-of-onset and duration of illness. In contrast, IL-2 production was reduced in each of the groups, although less so among atypical major depressives. Moreover, IL-2 production in the depressive groups was directly related to plasma NE levels. While neither depressed mood per se nor neurovegetative features accounted for this effect, it seemed likely that chronicity of illness or age-of-onset were associated with cytokine alterations. Given that circulating cytokines influence neuroendocrine functioning, and may affect neurovegetative features, a role for interleukins may exist with respect to the pathophysiology of certain subtypes of depression.

Meta-Analysis of the Reversible Inhibitors of Monoamine Oxidase Type A Moclobemide and Brofaromine for the Treatment of Depression

The reversible inhibitors of monoamine oxidase type A (RIMAs) are a newer group of antidepressants that have had much less impact on clinical psychopharmacology than another contemporary class of medications, the selective serotonin reuptake-inhibitors (SSRIs). The RIMAs agents are distinguished from the older monoamine oxidase inhibitors (MAOIs) by their selectivity and reversibility. As a result, dietary restrictions are not required during RIMA therapy, and hypertensive crises are quite rare. In this article, we describe a series of meta-analyses of studies of the two most widely researched RIMAs, moclobemide (MOC; Aurorex) and brofaromine (BRO). Our findings confirm that both BRO and MOC are as effective as the tricyclic antidepressants, and they are better tolerated. However, BRO is not being studied at present for reasons unrelated to efficacy or side effects. MOC, which is available throughout much of the world (but not the United States), is significantly more effective than placebo and, at the least, comparable to the SSRIs in both efficacy and tolerability. For MOC, higher dosages may enhance efficacy for more severe depressions. We also found evidence that supports clinical impressions that MOC is somewhat less effective, albeit better tolerated, than older MAOIs, such as phenelzine or tranylcypromine. Little evidence has yet emerged to suggest that the RIMAs share older MAOIs’ utility for treatment of depressions characterized by prominent reverse neurovegetative features. Based on available evidence, the RIMAs appear to have a limited, but useful, role in the differential therapeutics of the depressive disorders.