Abstracts For Major Depressive Disorder

Manji HK, Drevets WC, Charney DS

Major depressive disorders, long considered to be of neurochemical origin, have recently been associated with impairments in signaling pathways that regulate neuroplasticity and cell survival. Agents designed to directly target molecules in these pathways may hold promise as new therapeutics for depression.

Paykel ES

A consistent body of findings published over 30 years shows raised rates of life events before onset of clinical unipolar depression. A range of threatening events is implicated, with only limited specificity, although a somewhat closer relationship to interpersonal losses. Social support both buffers effects of life events and its absence also has some independent stressful effects. Life stress also affects outcome. Effects extend across the age range, but are weaker or absent in recurrent disorder, particularly when this is severe or melancholic. They are also weaker in bipolar disorder, where social rhythm disruption may have a particular effect. The causative contribution of life stress is of moderate size overall but does not exclude many other factors. Causative chains are complex and life stress itself is not fully independent, because available social support is shaped by personal capacity to form relationships, and occurrence of life events has some genetic elements and is predicted by disturbance in childhood.

Jick H, Kaye JA, Jick SS

Context: The relation between use of antidepressants, especially selective serotonin reuptake inhibitors (SSRIs), and suicidal ideation and behaviors has received considerable public attention recently. The use of such drugs among teenagers has been of particular concern. Objective: To estimate the relative risks (RRs) of nonfatal suicidal behavior in patients starting treatment with 1 of 3 antidepressant drugs compared with patients starting treatment with dothiepin. Design and setting: Matched case-control study of patients treated in UK general practices using the UK General Practice Research Database for 1993–1999. Participants: The base population included 159,810 users of the 4 antidepressant drugs. Participants could have used only 1 of these antidepressants and had to have received at least 1 prescription for the study antidepressant within 90 days before their index date (the date of suicidal behavior or ideation for cases and the same date for matched controls). Main outcome measures: Frequency of first-time exposure to amitriptyline, fluoxetine, paroxetine, and dothiepin of patients with a recorded diagnosis of first-time nonfatal suicidal behavior or suicide compared with comparable patients who did not exhibit suicidal behavior. Results: After controlling for age, sex, calendar time, and time from first antidepressant prescription to the onset of suicidal behavior, the relative risks for newly diagnosed nonfatal suicidal behavior in 555 cases and 2062 controls were 0.83 (95% confidence interval, [CI] 0.61-1.13) for amitriptyline, 1.16 (95% CI, 0.90-1.50) for fluoxetine, and 1.29 (95% CI, 0.97-1.70) for paroxetine compared with those using dothiepin. The RR for suicidal behavior among patients first prescribed an antidepressant within 1 to 9 days before their index date was 4.07 (95% CI, 2.89-5.74) compared with patients who were first prescribed an antidepressant 90 days or more before their index date. Time since first antidepressant prescription was not, however, a confounder of the relation between specific antidepressants and suicidal behavior since its relation to suicidal behavior was not materially different among users of the 4 study drugs. Similarly for fatal suicide, the RR among patients who were first prescribed an antidepressant within 1 to 9 days before their index date was 38.0 (95% CI, 6.2-231) compared with those who were first prescribed an antidepressant 90 days or more before their index date. There were no significant associations between the use of a particular study antidepressant and the risk of suicide. Conclusions: The risk of suicidal behavior after starting antidepressant treatment is similar among users of amitriptyline, fluoxetine, and paroxetine compared with the risk among users of dothiepin. The risk of suicidal behavior is increased in the first month after starting antidepressants, especially during the first 1 to 9 days. A possible small increase in risk (bordering statistical significance) among those starting the newest antidepressant, paroxetine, is of a magnitude that could readily be due to uncontrolled confounding by severity of depression. Based on limited information, we also conclude that there is no substantial difference in effect of the 4 drugs on people aged 10 to 19 years.

March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J; Treatment for Adolescents With Depression Study (TADS) Team

Context: Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. Objective: To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. Design, setting, and participants: Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Interventions: Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. Main outcome measures: Children’s Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results: Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P =.001) on the Children’s Depression Rating Scale-Revised. Compared with fluoxetine alone (P =.02) and CBT alone (P =.01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P =.01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [CI], 62%-80%); fluoxetine alone, 60.6% (95% CI, 51%-70%); CBT alone, 43.2% (95% CI, 34%-52%); and placebo, 34.8% (95% CI, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P =.02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusion: The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder.

Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH, Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM, Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J, Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K, Lebowitz BD, Ritz L, Niederehe G; STAR*D Investigators Group

STAR*D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are eligible for randomization to level 2 treatments, which entail four switch options (sertraline, bupropion, venlafaxine, cognitive therapy) and three citalopram augment options (bupropion, buspirone, cognitive therapy). Those who receive cognitive therapy (switch or augment options) at level 2 without sufficient improvement are eligible for randomization to one of two level 2A switch options (venlafaxine or bupropion). Level 2 and 2A participants are eligible for random assignment to two switch options (mirtazapine or nortriptyline) and to two augment options (lithium or thyroid hormone) added to the primary antidepressant (citalopram, bupropion, sertraline, or venlafaxine) (level 3). Those without sufficient improvement at level 3 are eligible for level 4 random assignment to one of two switch options (tranylcypromine or the combination of mirtazapine and venlafaxine). The primary outcome is the clinician-rated, 17-item Hamilton Rating Scale for Depression, administered at entry and exit from each treatment level through telephone interviews by assessors masked to treatment assignments. Secondary outcomes include self-reported depressive symptoms, physical and mental function, side-effect burden, client satisfaction, and health care utilization and cost. Participants with an adequate symptomatic response may enter the 12-month naturalistic follow-up phase with brief monthly and more complete quarterly assessments.

Montgomery SA, Baldwin DS, Riley A

Background: Sexual dysfunction is recognised as a potential side effect of antidepressant therapy. However, there is little detailed information on the prevalence of drug-induced sexual dysfunction or the differences, if any, between available drugs. This article is a critical review of the literature in the area. Methods: English-language studies on sexual dysfunction and depression or antidepressant treatments were identified by searching Medline and supplemented by manual review of their reference lists and recent journal issues available in a library. Trials of antidepressant use in anxiety disorders were identified from a Medline search and their adverse events tables scanned for data on sexual dysfunction. All trials were assessed according to predefined criteria. Results: Sexual dysfunction is widespread in the healthy non-depressed population and is a recognised symptom of depression and/or anxiety disorders. Sexual dysfunction has been reported with all classes of antidepressants (MAOIs, TCAs, SSRIs, SNRIs and newer antidepressants) in patients with depression and various anxiety disorders. Numerous studies have been published, but only one used a validated sexual function rating scale and most lacked either a baseline or a placebo control or both. None met all of the pre-defined assessment criteria. Limitations: The search techniques may have missed some studies and publication bias cannot be ruled out. Conclusions: The existing literature confirms sexual dysfunction as a possible adverse event of all antidepressants, but it is not sufficiently robust to support claims for differences in the incidence of drug-induced sexual dysfunctions between existing antidepressant therapies. Prescribing decisions should be based on a careful assessment of the benefits and risks of therapy in the individual patient.

Husain MM, Rush AJ, Fink M, Knapp R, Petrides G, Rummans T, Biggs MM, O’Connor K, Rasmussen K, Litle M, Zhao W, Bernstein HJ, Smith G, Mueller M, McClintock SM, Bailine SH, Kellner CH

Background: Remission of illness in patients with major depressive disorder (MDD) is achieved in less than half of patients initially treated with medication. Electroconvulsive therapy (ECT) is another treatment option. We report the speed of response and remission rates in a cohort of depressed patients who received a course of acute-phase ECT in the initial phase of an ongoing multicenter randomized trial of continuation ECT versus pharmacotherapy. Method: Patients with MDD according to DSM-IV criteria received bilateral ECT 3 times weekly. Prior to each treatment, a 24-item Hamilton Rating Scale for Depression (HAM-D-24) score was obtained by a clinical rater. Sustained response was defined as a > or = 50% reduction in baseline HAM-D-24 score for at least 2 and all subsequent measurement occasions. Remission was defined as HAM-D-24 scores of < or = 10 for at least the last 2 consecutive assessments. Data were collected from May 1997 through November 2000. Results: Of the 253 patients who entered the study, 86% (N = 217) completed the acute course of ECT. Sustained response occurred in 79% of the sample, and remission occurred in 75% of the sample (N = 253); 34% (85/253) of patients achieved remission at or before ECT #6 (week 2), and 65% (164/253) achieved remission at or before ECT #10 (weeks 3-4). Over half (54%; 136/253) had an initial first response by ECT #3 (end of week 1). Conclusion: ECT was associated with rapid response and remission in a high percentage of patients. ECT warrants early consideration in treatment algorithms for patients with MDD.

Fava M, Rankin MA, Wright EC, Alpert JE, Nierenberg AA, Pava J, Rosenbaum JF

The prevalence and clinical impact of anxiety disorder comorbidity in major depression were studied in 255 depressed adult outpatients consecutively enrolled in our Depression Research Program. Comorbid anxiety disorder diagnoses were present in 50.6% of these patients and included social phobia (27.0%), simple phobia (16.9%), panic disorder (14.5%), generalized anxiety disorder ([GAD] 10.6%), obsessive-compulsive disorder ([OCD] 6.3%), and agoraphobia (5.5%). While both social phobia and generalized anxiety preceded the first episode of major depression in 65% and 63% of cases, respectively, panic disorder (21.6%) and agoraphobia (14.3%) were much less likely to precede the first episode of major depression than to emerge subsequently. Although comorbid groups were not distinguished by depression, anxiety, hostility, or somatic symptom scores at the time of study presentation, patients with comorbid anxiety disorders tended to be younger during the index episode and to have an earlier onset of the major depressive disorder (MDD) than patients with major depression alone. Our results support the distinction between anxiety symptoms secondary to depression and anxiety disorders comorbid with major depression, and provide further evidence for different temporal relationships with major depression among the several comorbid anxiety disorders.

Lin KM

A growing number of studies clearly indicate the importance of race and ethnicity in the psychopharmacologic management of depression and anxiety disorders. The data highlight important pharmacokinetic, pharmacodynamic, and pharmacogenetic ethnic differences that may have profound implications for the efficacy and safety of psychotropic therapies. General treatment considerations based on these differences include greater attention to adverse event profiles, the possibility of improved clinical response at any given dose, and the potential need for lower starting doses and slower increases in dosage. Continued research in this area is clinically important as patients with increasingly divergent ethnic and cultural backgrounds seek treatment for a range of depressive and anxiety disorders.

Kornstein SG, Schatzberg AF, Thase ME, Yonkers KA, McCullough JP, Keitner GI, Gelenberg AJ, Ryan CE, Hess AL, Harrison W, Davis SM, Keller MB

Background: While the sex difference in prevalence rates of unipolar depression is well established, few studies have examined gender differences in clinical features of depression. Even less is known about gender differences in chronic forms of depression. Methods: 235 male and 400 female outpatients with DSM-III-R chronic major depression or double depression (i.e., major depression superimposed on dysthymia) were administered an extensive battery of clinician-rated and self-report measures. Results: Women were less likely to be married and had a younger age at onset and greater family history of affective disorder compared to men. Symptom profile was similar in men and women, with the exception of more sleep changes, psychomotor retardation and anxiety/somatization in women. Women reported greater severity of illness and were more likely to have received previous treatment for depression with medications and/or psychotherapy. Greater functional impairment was noted by women in the area of marital adjustment, while men showed more work impairment. Limitations: Since our population consisted of patients enrolling in a clinical trial, study exclusion criteria may have affected gender-related differences found. Conclusions: Chronicity of depression appears to affect women more seriously than men, as manifested by an earlier age of onset, greater family history of affective disorders, greater symptom reporting, poorer social adjustment and poorer quality of life. These findings represent the largest study to date of gender differences in a population with chronic depressive conditions.

Judd LL, Akiskal HS, Zeller PJ, Paulus M, Leon AC, Maser JD, Endicott J, Coryell W, Kunovac JL, Mueller TI, Rice JP, Keller MB

Background: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). Methods: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years’ systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. Results: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. Conclusions: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

Fava M

Treatment-resistant depression (TRD) typically refers to inadequate response to at least one antidepressant trial of adequate doses and duration. TRD is a relatively common occurrence in clinical practice, with up to 50% to 60% of the patients not achieving adequate response following antidepressant treatment. A diagnostic re-evaluation is essential to the proper management of these patients. In particular, the potential role of several contributing factors, such as medical and psychiatric comorbidity, needs to be taken into account. An accurate and systematic assessment of TRD is a challenge to both clinicians and researchers, with the use of clinician-rated or self-rated instruments being perhaps quite helpful. It is apparent that there may be varying degrees of treatment resistance. Some staging methods to assess levels of treatment resistance in depression are being developed, but need to be tested empirically.

Segal ZV, Pearson JL, Thase ME

On 21 and 22 May 2001, the National Institute of Mental Health convened a workshop to explore imminent scientific opportunities and encourage new research on preventing relapse in major depression, as a part of a larger effort to find treatments capable of producing durable long-term recovery from major depression. Participants considered definitional and developmental perspectives on depression relapse, the prophylactic potential of current treatments and their cost effectiveness and the neurobiological and psychological risk factors for episode return. It was recommended that the definition of the relapse construct be expanded to capture salient features of incomplete recovery or partial response to treatment that are associated with significant functional impairment. This information is often overlooked by the categorical criteria currently in use. With respect to interventions, there was support for sequencing pharmacological remission with psychological prophylaxis. Provision of focal, short-term treatments that embed relapse prevention skills augment the routes to effective prevention available to patients, beyond that afforded by continuation pharmacotherapy. The challenge will be to identify those subgroups of patients for whom each treatment algorithm is indicated. Finally, the link between basic science findings of biological and psychological markers of relapse vulnerability and treatment design needs to be strengthened. This could be accomplished by assessing patients in clinical prevention trials for the presence of, and changes in, relapse vulnerability markers, thereby providing direct, outcome-based data to gauge the protective value of different treatments that modify these markers.

Geddes JR, Carney SM, Davies C, Furukawa TA, Kupfer DJ, Frank E, Goodwin GM

Background: Antidepressant drugs can promote remission from acute depressive episodes. Our aim was to establish how long such treatments should be continued to prevent relapse. Method: We did a systematic overview of evidence from randomised trials of continuing treatment with antidepressants in patients with depressive disorders who have responded to acute treatment. Medline, Embase, Cinahl, PsycLIT, Psyndex, and Lilacs were searched. Findings: Data were pooled from 31 randomised trials (4410 participants). Continuing treatment with antidepressants reduced the odds of relapse by 70% (95% CI 62-78; 2p<0.00001) compared with treatment discontinuation. The average rate of relapse on placebo was 41% compared with 18% on active treatment. The treatment effect seemed to persist for up to 36 months, although most trials were of 12 months’ duration, and so the evidence on longer-term treatment requires confirmation. Significantly more participants allocated antidepressants withdrew from the trials than did those allocated to placebo (18% vs 15%, respectively; odds ratio 1.30, 95% CI 1.07-1.59): the treatment effect could be even greater in adherent patients. The two-thirds reduction in risk of depressive relapse seemed to be largely independent of the underlying risk of relapse, the duration of treatment before randomisation, or the duration of the randomly allocated therapy. Interpretation: Antidepressants reduce the risk of relapse in depressive disorder, and continued treatment with antidepressants would benefit many patients with recurrent depressive disorder. The treatment benefit for an individual patient will depend on their absolute risk of relapse with greater absolute benefits in those at higher risk. Further trials are needed to establish the optimum length of therapy and should include patients who were not well represented in these trials, including those at low risk of relapse.

Rothschild AJ

Major depression with psychotic features (MDpsy), a disorder with considerable morbidity and mortality, is more common than is generally realized and is a most difficult form of depression to treat. Patients with MDpsy exhibit more frequent relapses and recurrences and have increased use of services, greater disability, and a poorer clinical course when compared with nonpsychotically depressed patients. Patients with MDpsy demonstrate distinct biological abnormalities in studies of the hypothalamic-pituitary-adrenal (HPA) axis, dopaminergic activity, enzyme studies, brain imaging, electroencephalogram sleep profiles, and measures of serotonergic function when compared with nonpsychotic depression. The social and occupational impairment in MDpsy has been hypothesized to be secondary to subtle cognitive deficits caused by the higher cortisol levels frequently observed in MDpsy patients. Several studies support a relationship between bipolar disorder and MDpsy, particularly in young-onset MDpsy. The most efficacious treatments for MDpsy include the combination of an antidepressant and an antipsychotic, amoxapine, or electroconvulsive therapy. Atypical antipsychotic medications may have particular relevance for the treatment of MDpsy because of the potential for reduced risk of extrapyramidal side effects and tardive dyskinesia, as well as antipsychotic and possibly antidepressant qualities. Based on the observations that MDpsy patients exhibit marked dysregulation of the HPA axis and elevated cortisol levels, several antiglucocorticoid strategies have been employed to treat MDpsy patients. Many questions regarding the acute and long-term treatment of MDpsy remain for future studies to address.

Drevets WC

Neuroimaging technology has provided unprecedented opportunities for elucidating the anatomical correlates of major depression. The knowledge gained from imaging research and from the postmortem studies that have been guided by imaging data is catalyzing a paradigm shift in which primary mood disorders are conceptualized as illnesses that involve abnormalities of brain structure, as well as of brain function. These data suggest specific hypotheses regarding the neural mechanisms underlying pathological emotional processing in mood disorders. They particularly support a role for dysfunction within the prefrontal cortical and striatal systems that normally modulate limbic and brainstem structures involved in mediating emotional behavior in the pathogenesis of depressive symptoms.

Jindal RD, Thase ME

Sleep disturbances are almost always present in patients with depression. Though sleep disturbances generally abate with the resolution of depression, some patients continue to report poor sleep. Since a number of studies have demonstrated that insomnia increases the risk of new-onset depression and recurrence of depression, optimal management of insomnia associated with depression becomes an important clinical goal. Antidepressant agents have variable effects on sleep and in fact, some antidepressants seem to worsen sleep in patients with depression. This article reviews various treatment options in the management of patients presenting with insomnia and depression, including single agents, combination strategies and behavioral interventions.