Walter A. Brown

Severity of depression and response to antidepressants and placebo: An analysis of the food and Drug Administration database

Some studies suggest that more severely ill patients with depression respond well to antidepressants and poorly to placebo, whereas those who are mildly ill respond equally well to antidepressants and placebo. This notion has implications for the design of clinical trials. To further assess and substantiate these putative predictors of antidepressant and placebo response, we assessed the Food and Drug Administration database of 45 phase II and III antidepressant clinical trials. The frequency of statistically significant differences between antidepressants and placebo was higher in the trials that included patients with more severe depression. In the antidepressant-treated groups, the magnitude of symptom reduction was signif-icantly related to mean initial Hamilton Rating Scale for Depression (HAM-D) score; the higher the mean initial HAM-D score, the larger the change. With placebo treatment, however, the higher the mean initial HAM-D score, the smaller the change. Early discontinuation was more frequent among patients whose mean initial HAM-D scores were higher. These data may help inform the design of future antidepressant clinical trials.

Comparison of fluoxetine, bupropion, and placebo in the treatment of premenstrual dysphoric disorder.

Serotonergic antidepressants have been shown to be effective treatments for premenstrual dysphoric disorder (PMDD). The efficacy of nonserotonergic antidepressants is less well studied. This study was a two-center, parallel design, placebo-controlled, randomized trial of fluoxetine, bupropion, and placebo in women with PMDD. Thirty-four women with PMDD completed 1 month of single-blind placebo and 2 months of fluoxetine 20 mg/day (N = 10), bupropion 100 mg three times daily (N = 12), or placebo (N = 12). Clinical Global Impressions (CGI) Scale, an expanded form of the Hamilton Rating Scale for Depression (HAM-D), and Global Assessment Scale (GAS) ratings were obtained premenstrually in each of the three treatment cycles. The three treatment groups differed significantly in efficacy by CGI ratings. Fluoxetine was superior to both bupropion and placebo. Comparison of posttreatment to pretreatment HAM and GAS scores demonstrated significant superior efficacy of fluoxetine compared with placebo. Posttreatment HAM and GAS scores for bupropion were intermediate between but not significantly different from fluoxetine or placebo. In summary, fluoxetine was significantly superior to bupropion and placebo as an effective treatment for PMDD. Although some improvement with bupropion was noted, and both medications were well tolerated, patient satisfaction was far greater with fluoxetine.

Sex differences in antidepressant response in recent antidepressant clinical trials

Abstract: Some previous reports suggest that women respond differently than men to antidepressant treatment. Much of this literature compares men and womens response to tricyclics to that of newer antidepressants (SSRIs, SNRI), or only examines one particular antidepressant. This study compares men and womens responses to 6 newer antidepressants. A total of 15 randomized, placebo-controlled trials that included 323 depressed patients were examined for sex differences in antidepressant treatment response. Women had a significantly greater response than men to SSRI antidepressants. A similar trend was seen for those assigned to an SNRI antidepressant, although not to the same extent as with SSRI antidepressants. Although these gender differences in treatment response are not large enough to suggest that gender should guide the clinical use of SSRI and SNRI antidepressants, the results do have implications for the design and interpretation of antidepressant clinical trials. These findings also raise the possibility that antidepressants may work somewhat differently in men and women.

A Systematic Review of Comparative Efficacy of Treatments and Controls for Depression

Background Although previous meta-analyses have examined effects of antidepressants, psychotherapy, and alternative therapies for depression, the efficacy of these treatments alone and in combination has not been systematically compared. We hypothesized that the differences between approved depression treatments and controls would be small. Methods and Findings The authors first reviewed data from Food and Drug Administration Summary Basis of Approval reports of 62 pivotal antidepressant trials consisting of data from 13,802 depressed patients. This was followed by a systematic review of data from 115 published trials evaluating efficacy of psychotherapies and alternative therapies for depression. The published depression trials consisted of 10,310 depressed patients. We assessed the percentage symptom reduction experienced by the patients based on treatment assignment. Overall, antidepressants led to greater symptom reduction compared to placebo among both unpublished FDA data and published trials (F = 38.5, df = 239, p<0.001). In the published trials we noted that the magnitude of symptom reduction with active depression treatments compared to controls was significantly larger when raters evaluating treatment effects were un-blinded compared to the trials with blinded raters (F = 2.17, df = 313, p<0.05). In the blinded trials, the combination of antidepressants and psychotherapy provided a slight advantage over antidepressants (p = 0.027) and psychotherapy (p = 0.022) alone. The magnitude of symptom reduction was greater with psychotherapies compared to placebo (p = 0.019), treatment-as-usual (p = 0.012) and waiting-list (p<0.001). Differences were not seen with psychotherapy compared to antidepressants, alternative therapies or active intervention controls. Conclusions In conclusion, the combination of psychotherapy and antidepressants for depression may provide a slight advantage whereas antidepressants alone and psychotherapy alone are not significantly different from alternative therapies or active intervention controls. These data suggest that type of treatment offered is less important than getting depressed patients involved in an active therapeutic program. Future research should consider whether certain patient profiles might justify a specific treatment modality.

Are placebo controls necessary to test new antidepressants and anxiolytics

One measure of a treatments effectiveness is the regularity with which it proves superior to placebo. That measure also tells us about the consequences of using a treatment as a standard against which to test a new agent. To assess the frequency with which approved and presumably effective antidepressants and anxiolytics show statistical superiority over placebo, we reviewed placebo-controlled clinical trials of antidepressants and anxiolytics in a singularly large database free of publication bias. We evaluated clinical-trial data from the nine antidepressants approved by the FDA between 1985 and 2000. These trials comprised 10030 depressed patients who participated in 52 antidepressant clinical trials evaluating 93 treatment arms of a new or established antidepressant. Similarly, we examined clinical trials data from the 13 anxiolytics approved by the FDA between 1985 and 2000. These trials comprised 8,340 anxious patients, 40 anxiolytic clinical trials and 75 treatment arms of a new or established anxiolytic. Fewer than half (48%, 45/93) of the antidepressant treatment arms showed superiority to placebo. Among anxiolytics, 48% (36/75) of anxiolytic treatment arms showed superiority over placebo. These data suggest that conventional psychopharmacologic treatments for depression and anxiety are superior to placebo less than half the time and call into serious question the widely propagated notion that placebo controls can be dispensed with in clinical trials of these agents. Exclusion of placebo controls in favour of non-inferiority trials would result in a high likelihood that ineffective antidepressants and anxiolytics would be foisted on the public and, less dangerous but also problematic, that potentially effective agents would be missed.

Issues for DSM-5: Whither Melancholia? The Case for Its Classification as a Distinct Mood Disorder

Melancholia, a syndrome with a long history and distinctly specific psychopathological features, is inadequately differentiated from major depression by the DSM-IV specifier. It is neglected in clinical assessment (e.g., in STAR*D [1]) and treatment selection (e.g., in the Texas Medication Algorithm Project [2]). Nevertheless, it possesses a distinctive biological homogeneity in clinical experience and laboratory test markers, and it is differentially responsive to specific treatment interventions. It therefore deserves recognition as a separate identifiable mood disorder. Melancholia has been variously described as “endogenous,” “endogenomorphic,” “autonomous,” “type A,” “psychotic,” and “typical” depression (3–6). In contrast to the current DSM criteria for the melancholia specifier (features of which are often shared with major depression), it has characteristic clinical features (5–7).

Suicide risk in patients with anxiety disorders: a meta-analysis of the FDA database

BACKGROUND Previous reports of suicide risk in patients with anxiety disorders have been inconsistent. METHODS Using the FDA database, we assessed suicide and suicide attempt risk among patients, participating in recent clinical trials evaluating new anti-anxiety medications, with diagnosis of panic disorder (PD), social anxiety disorder or social phobia (SP), generalized anxiety disorder (GAD), post traumatic stress disorder (PTSD), and obsessive compulsive disorder (OCD). RESULTS Overall, among 20076 participating anxious patients, 12 committed suicide and 28 attempted suicide. The annual suicide risk rate was 193/100000 patients and annual suicide attempt risk was 1350/100000 patients. LIMITATIONS Clinical trial data have limited applicability to clinical practice. Participants in clinical trials are a highly selected, nonrepresentative sample of the clinical population. A number of patients never complete clinical trials and thus data are based on a limited sub-sample. These trials were not primarily designed to assess suicide risk. CONCLUSIONS Suicide risk in patients with anxiety disorders is higher than previously thought. Patients with anxiety disorders warrant explicit evaluation for suicide risk.

Clinical features of depressed patients who do and do not improve with placebo

The substantial placebo response in depression confounds treatment decisions and the assessment of new therapies. Improvement with placebo occurs infrequently in patients with chronic depression and in those with pituitary-adrenocortical hyperfunction, but other consistent predictors of placebo response have not been detected. We divided 241 moderately to severely depressed patients who had received placebo on a double-blind basis for 3 to 6 weeks into responders (greater than or equal to 50% improvement in Hamilton depression score, final Hamilton depression score less than or equal to 10), extreme nonresponders (less than 25% improvement), and partial responders (all others). Improvement with placebo was associated with a relatively short illness, a precipitating event, depression of only moderate global severity, and a good response to previous antidepressant treatment. These observations suggest that depressed patients who do and do not recover with placebo have different conditions that have not yet been fully characterized.

Pituitary-adrenal disinhibition in depression: Marker of a subtype with characteristic clinical features and response to treatment?

The data from a series of studies in different patient samples are consistent in showing that resistance to dexamethasone suppression is selectively associated with primary major depressive disorder. In addition, nonsuppressors appear to have more depressive episodes, show greater improvement during hospitalization, tend to be older than suppressors, and may have a specific disturbance in cognitive function. Preliminary data suggest that nonsuppressors and suppressors respond preferentially to different antidepressants. These data raise the possibility that pituitary-adrenal disinhibition, as assessed by the dexamethasone suppression test, is associated with a depressive subtype having a distinctive pathophysiology, clinical course, and treatment response.

Serum testosterone and sexual activity and interest in men.

There is considerable interest in the relationship between testosterone and sexual behavior in men, but the few available data bearing on this issue are inconclusive. This study is an attempt to clarify the relationships among various components of sexuality and serum testosterone concentration through examination of these variables in a large homogeneous group of men. Serum testosterone concentration was determined in two blood samples taken 1 week apart from 101 young adult men. Subjects reported their frequencies of various sexual activities and level of sexual interest. Testosterone concentrations in the two blood samples were highly correlated, indicating considerable intraindividual consistency. There was considerable variance among subjects in both mean testosterone and reported sexual activity. Testosterone concentration did not correlate with the sexual activity and interest variables. These results provide evidence that differences among men in circulating testosterone concentration within the normal range do not account for differences in sexual activity and interest. It is also unlikely that variations in sexual activity account for differences in testosterone concentration.