Shamsah B. Sonawalla

Comparing anxiety disorders and anxiety-related traits in bipolar disorder and unipolar depression

The frequent comorbidity of anxiety disorders and mood disorders has been documented in previous studies. However, it remains unclear whether specific anxiety traits or disorders are more closely associated with unipolar major depression (MDD) or bipolar disorder (BPD). We sought to examine whether MDD and BPD can be distinguished by their association with specific types of anxiety comorbidity. Individuals with a primary lifetime diagnosis of either bipolar disorder (N=122) or major depressive disorder (N=114) received diagnostic assessments of anxiety disorder comorbidity, and completed questionnaires assessing anxiety sensitivity and neuroticism. The differential association of these anxiety phenotypes with MDD versus BPD was examined with multivariate modeling. Panic disorder and generalized anxiety disorder (GAD) specifically emerged amongst all the anxiety disorders as significantly more common in patients with BPD than MDD. After controlling for current mood state, anxiety sensitivity and neuroticism did not differ by mood disorder type. This study supports prior research suggesting a specific panic disorder-bipolar disorder connection, and suggests GAD may also be differentially associated with BPD. Further research is needed to clarify the etiologic basis of anxiety disorder/BPD comorbidity and to optimize treatment strategies for patients with these co-occurring disorders.

Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine.

In a previous study, of 41 depressed patients who had not responded to fluoxetine 20 mg/day, 53% were treated with high-dose fluoxetine (40–60 mg/ day) and responded (i.e., their 17-item Hamilton Rating Scale for Depression [HAM-D-17] score was <7) versus 29% and 25% of patients treated with fluoxetine plus lithium (300–600 mg/day) or fluoxetine plus desipramine (25–50 mg/day), respectively. We wanted to assess whether these findings could be replicated in a larger sample of depressed outpatients. We identified 101 outpatients with major depressive disorder (52 men and 49 women; mean age, 41.6 + 10.6 years) who were either partial responders (n = 49) or nonresponders (n = 52) to 8 weeks of treatment with fluoxetine 20 mg/ day. These patients were randomized to 4 weeks of double-blind treatment with high-dose fluoxetine (40–60 mg/day), fluoxetine plus lithium (300–600 mg/day), or fluoxetine plus desipramine (25–50 mg/day). In the overall group of patients (N = 101), there was no significant difference in response rates across the three treatment groups (high-dose fluoxetine, 42.4%; fluoxetine plus desipramine, 29.4%; fluoxetine plus lithium, 23.5%). Dropout rates were also comparable, ranging from 9.1% (high-dose fluoxetine) to 14.7% (fluoxetine plus desipramine and fluoxetine plus lithium). There were also no significant differences in response rates across the three treatment groups among partial responders (high-dose fluoxetine, 50.0%; fluoxetine plus desipramine, 33.3%; fluoxetine plus lithium, 33.3%) and nonresponders (high-dose fluoxetine, 35.3%; fluoxetine plus desipramine, 26.3%; fluoxetine plus lithium, 12.5%). At the end of the study, the mean lithium level was 0.37 + 0.15 mEq/L (n = 27; range, 0.1–0.8 mEq/L) among lithium-treated patients, and the mean desipramine level was 104.7 + 58.8 ng/mL (n = 22; range, 25–257 ng/mL). There were no significant relationships between lithium or desipramine blood levels and degree of improvement (as measured by the change in HAM-D-17 score). We found no significant differences in efficacy among these three treatment strategies among patients who had failed to respond adequately to 8 weeks of treatment with fluoxetine 20 mg/day, although the high-fluoxetine group was associated with nonsignificantly higher response rates in both partial responders and nonresponders.

Personality disorders and depression.

BACKGROUND Personality disorders (PDs) were assessed among depressed out-patients by clinical interview before and after antidepressant treatment with fluoxetine to assess the degree of stability of PD diagnoses and determine whether changes in PD diagnoses across treatment are related to the degree of improvement in depressive symptoms. METHOD Three hundred and eighty-four out-patients (55% women; mean age = 39.9 +/- 10.5) with major depressive disorder (MDD) diagnosed with the SCID-P were enrolled into an 8 week trial of open treatment with fluoxetine 20 mg/day. The SCID-II was administered to diagnose PDs at baseline and endpoint. RESULTS A significant proportion (64%) of our depressed out-patients met criteria for at least one co-morbid personality disorder. Following 8 weeks of fluoxetine treatment, there was a significant reduction in the proportion of patients meeting criteria for avoidant, dependent, passive-aggressive, paranoid and narcissistic PDs. From baseline to endpoint, there was also a significant reduction in the mean number of criteria met for paranoid, schizotypal, narcissistic, borderline, avoidant, dependent, obsessive-compulsive, passive aggressive and self-defeating personality disorders. While changes in cluster diagnoses were not significantly related to improvement in depressive symptoms, there were significant relationships between degree of reduction in depressive symptoms (percentage change in HAM-D-17 scores) and degree of change in the number of criteria met for paranoid, narcissistic, borderline and dependent personality disorders. CONCLUSIONS Personality disorder diagnoses were found to be common among untreated out-patients with major depressive disorder. A significant proportion of these patients no longer met criteria for personality disorders following antidepressant treatment, and changes in personality disorder traits were significantly related to degree of improvement in depressive symptoms in some but not all personality disorders. These findings suggest that the lack of stability of PD diagnoses among patients with current MDD may be attributable in part to a direct effect of antidepressant treatment on behaviours and attitudes that comprise PDs.

A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder

We examined the antidepressant efficacy and dose-response pattern of the n-3 docosahexaenoic acid (DHA). Thirty-five depressed adult outpatients (46% women; mean age 42+/-14 years) with a 17-item Hamilton-Depression Scale (HAM-D-17) score of >or=18 were randomized into one of three double-blind dosing arms for 12 weeks. Group A (n=14): 1 g/day of oral DHA; Group B (n=11): 2 g/day; and Group C (n=10): 4 g/day. We measured HAM-D-17 scores, plasma DHA, eicosapentaenoic acid (EPA), and n-6/n-3 ratio. Completer response rates (>or=50% decrease in HAM-D-17 score) were 83% for Group A, 40% for Group B, and 0% for Group C; Groups A and B had significant decreases in HAM-D-17 scores (p<0.05). For completers and intent-to-treat subjects, plasma DHA increased significantly (p<0.05), EPA had little change (p>0.05), and n-6/n-3 decreased significantly (p<0.05). DHA may be effective for depression at lower doses.

Use of the Chinese version of the Beck Depression Inventory for screening depression in primary care.

Many Asian-Americans are unfamiliar with depression and its treatment. When depressed, they generally seek treatment from their primary care physicians and complain about their physical symptoms, resulting in under-recognition and under-treatment of depression. This study evaluates the effectiveness of the Chinese version of the Beck Depression Inventory (CBDI) for screening depression among Chinese-Americans in primary care. A total of 503 Chinese-Americans in the primary care clinic of a community health center were administered the CBDI for depression screening. Patients who screened positive (CBDI ≥ 16) were interviewed by a psychiatrist using the Structured Clinical Interview for DSM-III-R, patient version (SCID-I/P) for confirmation of the diagnosis. Patients who screened negative (CBDI < 16) were randomly selected to be interviewed using the depression module of the SCID-I/P. The results of the SCID-I/P interview were used as the standard for evaluating the sensitivity and specificity of the CBDI. A total of 815 Chinese-Americans in a primary care clinic were approached, and 503 completed the CBDI. Seventy-six (15%) screened positive (CBDI ≥ 16), and the prevalence of major depression was 19.6% by using extrapolated results from SCID-I/P interviews. When administered by a native-speaking research assistant, the CBDI has good sensitivity (.79), specificity (.91), positive predictive value (.79), and negative predictive value (.91). Despite the commonly believed tendency to focus on physical symptoms rather than depressed mood, Chinese-Americans are able to report symptoms of depression in response to a questionnaire. The CBDI, when administered by research assistants, has good sensitivity and specificity in recognizing major depression in this population. Lack of interest among Chinese-American patients in using the CBDI as a self-rating instrument has limited its use for depression screening in primary care settings.

Severe depression: Is there a best approach?

A major depressive episode can be categorised as severe based on depressive symptoms, scores on depression rating scales, the need for hospitalisation, depressive subtypes, functional capacity, level of suicidality and the impact that the depression has on the patient. Several biological, psychological and social factors, and the presence of comorbid psychiatric or medical illnesses, impact on depression severity.A number of factors are reported to influence outcome in severe depression, including duration of illness before treatment, severity of the index episode, treatment modality used, and dosage and duration of and compliance with treatment. Potential complications of untreated severe depression include suicide, self-mutilation and refusal to eat, and treatment resistance.Several antidepressants have been studied in the treatment of severe depression. These include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline (norepinephrine) reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin 5-HT2 receptor antagonists, monoamine oxidase inhibitors, and amfebutamone (bupropion). More recently, atypical antipsychotics have shown some utility in the management of severe and resistant depression.Data on the differential efficacy of TCAs versus SSRIs and the newer antidepressants in severe depression are mixed. Some studies have reported that TCAs are more efficacious than SSRIs; however, more recent studies have shown that TCAs and SSRIs have equivalent efficacy. There are reports that some of the newer antidepressants may be more effective than SSRIs in the treatment of severe depression, although the sample sizes in some of these studies were small. Combination therapy has been reported to be effective. The use of an SSRI-TCACombination, while somewhat controversial, may rapidly reduce depressive symptoms in some patients with severe depression. The combination of an anti-depressant and an antipsychotic drug is promising and may be considered for severe depression with psychotic features.Although the role of cognitive behaviour therapy (CBT) in severe depression has not been adequately studied, a trial of CBT may be considered in severely depressed patients whose symptoms respond poorly to an adequate antidepressant trial, who are intolerant of antidepressants, have contraindications to pharmaco-therapy, and who refuse medication or other somatic therapy. A combination of CBT and antidepressants may also be beneficial in some patients.Electroconvulsive therapy (ECT) may be indicated in severe psychotic depression, severe melancholic depression, resistant depression, and in patients intolerant of antidepressant medications and those with medical illnesses which contraindicate the use of antidepressants (e.g. renal, cardiac or hepatic disease).

A Double-Blind, Randomized, Pilot Dose-Finding Study of Maca Root (L. Meyenii) for the Management of SSRI-Induced Sexual Dysfunction

We sought to determine whether maca, a Peruvian plant, is effective for selective‐serotonin reuptake inhibitor (SSRI)‐induced sexual dysfunction. We conducted a double‐blind, randomized, parallel group dose‐finding pilot study comparing a low‐dose (1.5 g/day) to a high‐dose (3.0 g/day) maca regimen in 20 remitted depressed outpatients (mean age 36 ± 13 years; 17 women) with SSRI‐induced sexual dysfunction. The Arizona Sexual Experience Scale (ASEX) and the Massachusetts General Hospital Sexual Function Questionnaire (MGH‐SFQ) were used to measure sexual dysfunction. Ten subjects completed the study, and 16 subjects (9 on 3.0 g/day; 7 on 1.5 g/day) were eligible for intent‐to‐treat (ITT) analyses on the basis of having had at least one postbaseline visit. ITT subjects on 3.0 g/day maca had a significant improvement in ASEX (from 22.8 ± 3.8 to 16.9 ± 6.2; z =−2.20, P= 0.028) and in MGH‐SFQ scores (from 24.1 ± 1.9 to 17.0 ± 5.7; z =−2.39, P= 0.017), but subjects on 1.5 g/day maca did not. Libido improved significantly (P < 0.05) for the ITT and completer groups based on ASEX item #1, but not by dosing groups. Maca was well tolerated. Maca root may alleviate SSRI‐induced sexual dysfunction, and there may be a dose‐related effect. Maca may also have a beneficial effect on libido.

Somatic symptoms in treatment-resistant depression

The purpose of this work was to study the prevalence of somatic symptoms in patients with treatment-resistant depression (TRD) and their impact on the response to antidepressant treatment. Somatic symptoms were assessed during the screen visit with the Symptom Questionnaire (SQ) somatic symptom (SQ-SS) and somatic well-being sub-scales (SQ-SWB) in 40 patients with TRD enrolled in a 6-week open trial of nortriptyline. A logistic regression was used to test whether SQ-SS or SQ-SWB scores predicted clinical response to nortriptyline. Ninety-five percent of patients reported at least one somatic symptom. Higher SQ-SS scores during the screen visit predicted poorer response to nortriptyline. There was a trend for lower SQ-SWB scores to predict poor response to nortriptyline. None of the patients with SQ-SS scores above the mean for the sample responded to nortriptyline. The overwhelming majority of patients with TRD presented with somatic symptoms. In addition, a greater number of somatic symptoms during the screen visit placed patients at risk for further treatment resistance.

Serum cholesterol in treatment-resistant depression.

Objective: Patients with major depressive disorder (MDD) may have significant differences in cholesterol levels compared with healthy controls. A previous study by our group reported that depressed patients with elevated cholesterol levels (≧200 mg/dl) were significantly more likely to be nonresponders to fluoxetine treatment than depressed patients with nonelevated cholesterol levels. However, very little is known regarding cholesterol in patients with treatment-resistant depression (TRD). The purpose of this study was to compare cholesterol levels at baseline between depressed patients with and without TRD and to test whether cholesterol levels at baseline can predict clinical response in patients with TRD treated with open-label nortriptyline (NT). Methods: Ninety-two patients with TRD entered a 6-week open trial of NT. Baseline cholesterol levels were randomly collected for 59 of these patients. Controlling for age and gender, we compared baseline cholesterol and triglyceride levels for 35 patients with TRD who did not respond to NT with 205 non-TRD patients who responded to an 8-week open trial of fluoxetine. Furthermore, with the use of logistic regression, we tested whether baseline cholesterol levels predicted clinical response to NT in the patients with TRD. Results: Patients with TRD had higher triglyceride levels at baseline compared with depressed patients without TRD. Cholesterol defined as a dichotomous variable being elevated if equal to or greater than 200 mg/dl, predicted poor response to a 6-week open trial of NT in patients with TRD. Conclusions: The results of this study confirm the relationship between hypercholesterolemia and poor outcome in the treatment of MDD for patients with TRD.

An open pilot study of nefazodone in depression with anger attacks: relationship between clinical response and receptor binding

Nefazodone has been widely used as an antidepressant, but it has not been tested for depression with anger attacks. In an open study, we administered nefazodone (maximum 600 mg/day) for 12 weeks to 16 outpatients who had major depression with anger attacks. Assessment instruments comprised the Structured Clinical Interview for DSM-IV (SCID), Anger Attacks Questionnaire (AAQ), 17-item Hamilton Rating Scale for Depression (HAM-D-17), Clinician Global Impression Scale (CGI), Symptom Questionnaire (SQ), Modified Overt Aggression Scale (MOAS), and MOAS-Self-Rated. Three subjects underwent positron emission tomography (PET) with [18F]-setoperone for 5-HT2 binding potential (BP) and [11C]-SCH-23,390 for D1 BP, both at baseline and after 6 weeks of treatment. Eight subjects underwent PET with [18F]-setoperone and with [11C]-SCH-23,390 at baseline only. In an examination of whether D1 and 5HT2 (data available in six subjects) receptor BP predicted treatment response, we found significant decreases in the HAM-D-17, CGI-S, weighted MOAS, MOAS verbal scale, OAS Self-Rated verbal, SQ Depression and Anger/Hostility scales after nefazodone; 50% responded to nefazodone (defined as >or=50% decrease in HAM-D-17 score), and 44% reported disappearance of anger attacks. A statistically significant percentage decrease in 5HT2 BP was observed for the right mesial frontal and left parietal regions after 6 weeks of treatment. No significant change was observed in D1 BP in any region. Although CGI-I scores correlated significantly with D1 BP in the left thalamic region, the correlation was not significant after Bonferroni correction. The effectiveness of nefazodone for depression with anger attacks may be related to widespread changes in 5HT2 receptor BP.