Targeted genome screen of panic disorder and anxiety disorder proneness using homology to murine QTL regions.

Family and twin studies have indicated that genes influence susceptibility to panic and phobic anxiety disorders, but the location of the genes involved remains unknown. Animal models can simplify gene-mapping efforts by overcoming problems that complicate human pedigree studies including genetic heterogeneity and high phenocopy rates. Homology between rodent and human genomes can be exploited to map human genes underlying complex traits. We used regions identified by quantitative trait locus (QTL)-mapping of anxiety phenotypes in mice to guide a linkage analysis of a large multiplex pedigree (99 members, 75 genotyped) segregating panic disorder/agoraphobia. Two phenotypes were studied: panic disorder/agoraphobia and a phenotype ("D-type") designed to capture early-onset susceptibility to anxiety disorders. A total of 99 markers across 11 chromosomal regions were typed. Parametric lod score analysis provided suggestive evidence of linkage (lod = 2.38) to a locus on chromosome 10q under a dominant model with reduced penetrance for the anxiety-proneness (D-type) phenotype. Nonparametric (NPL) analysis provided evidence of linkage for panic disorder/agoraphobia to a locus on chromosome 12q13 (NPL = 4.96, P = 0.006). Modest evidence of linkage by NPL analysis was also found for the D-type phenotype to a region of chromosome 1q (peak NPL = 2.05, P = 0.035). While these linkage results are merely suggestive, this study illustrates the potential advantages of using mouse gene-mapping results and exploring alternative phenotype definitions in linkage studies of anxiety disorder.

Patterns of axis I comorbidity in early-onset versus late-onset major depressive disorder.

BACKGROUND: This study of a large clinical sample of depressed patients examined whether childhood onset as compared with adult onset Major Depressive Disorder (MDD) would confer a greater risk for Axis I comorbidity and whether childhood onset MDD would also differ from adult onset MDD in the pattern of comorbid disorders. METHODS: We examined lifetime co-occurrence of Axis I disorders among 381 adult outpatients with MDD by Structured Clinical Interview for DSM-III-R-Patient Edition (SCID-P). Subjects were divided into childhood onset (n = 47), adolescent onset (n = 101) and adult onset (n = 233) MDD groups. RESULTS: We found that the two early-onset groups exhibited significantly increased rates of Axis I comorbidity. The childhood onset group accounted for a disproportionately high percentage of depressed adults with two or more comorbid Axis I disorders. Social and simple phobias and alcohol abuse/dependence were significantly more prevalent among individuals with childhood onset MDD than among individuals with adult onset MDD. Alcohol abuse/dependence, but not anxiety disorders, was significantly more prevalent among adolescent onset than adult onset MDD groups. Panic, generalized anxiety, obsessive-compulsive and somatoform disorders were equally distributed across MDD onset groups. Comorbid disorders were much more likely to have followed onset of MDD among individuals with childhood compared with adult onset, except for social phobia which more frequently preceded the depression. The relative ordering among the comorbid conditions with respect to whether they followed or preceded MDD did not vary notably across the three age of onset groups. CONCLUSIONS: We conclude that early-onset MDD is associated with an increased density of Axis I comorbidity that seems to be limited to specific disorders.

Residual symptoms in depressed patients who respond acutely to fluoxetine.

BACKGROUND: Antidepressants have unequivocal efficacy as compared with placebo, but many patients have residual symptoms despite a robust response to antidepressant therapy. The purpose of this study is to assess residual symptoms in outpatients who respond acutely to fluoxetine. METHOD: Two hundred and fifteen outpatients with major depressive disorder as assessed with the Structured Clinical Interview for DSM-III-R (SCID-P) were treated openly with fluoxetine 20 mg/day for 8 weeks. One hundred and eight (50.2%) were considered full responders (final 17-item Hamilton Rating Scale for Depression [HAM-D] score < or =7). Percentages of full responders who continued to have subthreshold or full major depressive disorder symptoms were calculated. The relationship between residual symptoms and Axis I and Axis II (assessed with SCID-II for personality disorders) comorbidity was assessed. RESULTS: Of the 108 responders, 19 (17.6%) had no subthreshold or threshold SCID-P major depressive disorder symptoms, while 28 (25.9%) had 1 symptom, and 61 (56.5%) had 2 or more symptoms. No statistically significant relationships were found between number of residual symptoms and selected Axis I comorbid conditions or total number of Axis II disorders. CONCLUSION: Less than 20% of full responders to fluoxetine by HAM-D criteria were free of all SCID-P subthreshold and threshold major depressive disorder symptoms after 8 weeks of treatment. While depressed patients benefit from antidepressants, most continue to have some symptoms of depression. The high prevalence of residual symptoms among antidepressant responders suggests the need for further study including whether residual symptoms abate with longer treatment or increased dose of fluoxetine. Other strategies, such as cognitive behavioral therapy, may be needed to address residual symptoms.

Major depressive subtypes and treatment response.

The purpose of this study was to investigate the relationships between depressive subtypes and response to fluoxetine treatment in a large cohort of outpatients. We studied 294 outpatients with major depressive disorder who were then treated with fluoxetine 20 mg/day for 8 weeks. Treatment outcome was evaluated with the Hamilton Depression Rating Scale (HDRS)-17, the Clinical Global Impressions-Severity, and with the HDRS-8; the latter is proposed to be a relatively more specific measure of depression severity than the HDRS-17. We assessed the relationships between degree of treatment response and several depressive subtypes (melancholic, atypical, hostile, and anxious depression, double depression, and depression with comorbid personality disorders), after adjusting for baseline depression severity. We found that nonanxious depressives (patients without any comorbid anxiety disorder) improved slightly but significantly more during treatment than anxious depressives on all outcome measures. Melancholic depression was associated with slightly less improvement on the HDRS-17 only, whereas the other subtypes of depression were not associated with differences in treatment outcome.

Social phobia, avoidant personality disorder and atypical depression: co-occurrence and clinical implications.

BACKGROUND: Increasing attention has been directed in recent years to the detection and treatment of psychiatric co-morbidity among depressed individuals. The overlap of social phobia (SP) and avoidant personality disorder (APD) has been well recognized and a relationship between these disorders and depression has been suggested. METHODS: The pattern and clinical implications of co-morbidity of SP and APD with major depressive disorder (MDD), diagnosed by DSM-III-R criteria, were studied among 243 out-patients presenting with depression. RESULTS: Overall, 26.7% of adults in our sample with MDD met criteria for SP and 28.4% for APD. Almost two-thirds of depressed adults meeting criteria for social phobia or avoidant personality disorder met criteria for both (SP+APD). Depressed adults who met criteria for both SP+APD exhibited a significantly higher proportion of atypical depression (54.8%) compared with those with neither SP nor APD (31.1%). Among depressed patients, the co-occurrence of SP with APD was also associated with an earlier age of onset of MDD, a greater number of comorbid Axis I diagnoses, and greater impairment of social adjustment and assertiveness. CONCLUSIONS: Results confirm the overlap of SP and APD in a depressed population and the high prevalence of these disorders in MDD. They suggest that depressed individuals with both SP and APD but not SP alone are at particularly high risk for atypical depression and for social dysfunction in excess of that caused by a current major depression.

Are dependency and self-criticism risk factors for major depressive disorder?

OBJECTIVE: To determine whether dependent and self-critical personality traits are associated with specific types of life events and whether these traits change with pharmacotherapy. METHOD: Overall, 142 depressed outpatients completing 8 weeks of fluoxetine treatment were administered the Life Experiences Survey (LES) at baseline and the Dysfunctional Attitude Scale (DAS) and Hamilton Depression Rating Scale (HDRS) at baseline and endpoint. RESULTS: The DAS dependency subscale, but not the self-criticism subscale, showed significant correlations with life events regardless of congruency. Baseline HDRS scores were positively correlated with both DAS subscales and total score. The DAS subscales, the total DAS score, and the HDRS all improved significantly with treatment. CONCLUSIONS: These results confirm a growing body of research that has found an association between sociotropic or dependent personality traits and life events.

Eating disorder symptomatology in major depression.

This study evaluated the relationship between eating disorder symptomatology and severity of depression in depressed outpatients before and after antidepressant treatment and assessed the effect of treatment on eating disorder symptomatology. One hundred thirty-nine outpatients (82 women and 57 men) with major depressive disorder (MDD) filled out the eating disorder inventory (EDI) before and after 8 weeks of treatment with fluoxetine 20 mg/day. Diagnoses of MDD and possible comorbid eating disorders were made with the Structured Clinical Interview for DSM-III-R-Patient Edition. Several EDI subscales correlated significantly with severity of depression both at baseline and endpoint. Additionally, all EDI subscales showed a statistically significant decrease following fluoxetine treatment, and changes in depression severity following treatment were significantly related to changes in EDI bulimia, ineffectiveness, perfectionism, and interpersonal distress subscale scores. These results suggest that several symptoms characteristic of eating disordered patients are linked to the severity of depressive symptoms. Decreases in eating disorder symptomatology following antidepressant treatment may be related to changes in depressive symptoms.

Consumption of alcohol, nicotine, and caffeine among depressed outpatients. Relationship with response to treatment.

The authors present findings from the first investigation of the use of alcohol, nicotine, and caffeine in nonsubstance-abusing outpatients with major depressive disorder. The patients (N = 94) were assessed for their intake of alcohol, nicotine, and caffeine, and then treated openly for 8 weeks with 20 mg/day of fluoxetine. The degree of alcohol consumption at baseline was a significant predictor of poorer response to the antidepressant. This relationship remained significant even after adjusting for severity of depression at baseline. Even moderate levels of alcohol consumption appear to negatively affect pharmacologic treatment in depressed outpatients.

Patterns of personality disorder comorbidity in early-onset versus late-onset major depression.

OBJECTIVE: This study tested the hypothesis that in a population of adult outpatients with major depression, those with an early onset of depression would have a greater prevalence of personality disorders than those with a late onset of depression. METHOD: The 404 subjects were patients participating in depression treatment studies at the Massachusetts General Hospital. They were administered the Structured Clinical Interview for DSM-III-R-Patient Version to assess the current presence of major depression and the age at onset of the initial depressive episode. The subjects were then divided into two groups: those with early onset (before 18 years of age) and those with late onset (at age 18 or later). The prevalence of personality disorders was determined through use of the physician-rated Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II) and the patient-rated Personality Diagnostic Questionnaire-Revised (PDQ-R). RESULTS: The patients with early onset of major depression had a significantly higher prevalence of avoidant, histrionic, narcissistic, and borderline personality disorders according to the SCID-II. The PDQ-R scores indicated that avoidant, dependent, passive-aggressive, histrionic, narcissistic, borderline, and antisocial personality disorders were significantly more prevalent among the patients with early onset of major depression. CONCLUSIONS: Overall, the results are consistent with the view that early-onset depressive illness is distinguished from late-onset major depression by more frequent association with persistent disturbances in behaviors and attitudes.

Are neurovegetative symptoms stable in relapsing or recurrent atypical depressive episodes?

Few data exist that assess the presence of reversed and positive neurovegetative symptoms through successive depressive episodes. To assess the stability of depressive symptoms across episodes, we studied 74 outpatients with atypical unipolar major depression, diagnosed by the Structured Clinical Interview for DSM-III-R, before response to fluoxetine treatment and again after relapse on either fluoxetine or placebo. Patients were assessed at baseline with the Atypical Depression Diagnosis Scale and at baseline and during follow-up with the 17-item Hamilton Rating Scale for Depression. Thirty-two (43%) of responders had a relapse or recurrence, 21 (66%) of whom had a predominance of reversed of positive neurovegetative symptoms at baseline. Nine of 10 (90%) patients with reversed symptoms at baseline had the same symptoms when they relapsed; seven of 11 (64%) of those with positive symptoms at baseline had positive symptoms again (kappa 0.557). Overall, five of 21 (24%) had changes in their disturbances in sleep, appetite, or weight when they relapsed. This study supports the relative stability of neurovegetative symptoms in atypical depression across episodes.

Gender differences in Axis I comorbidity among depressed outpatients.

OBJECTIVE: The aim of our study was to assess gender differences in Axis I comorbidity in patients with a primary diagnosis of Major Depressive Disorder (MDD), as well as gender differences in age of onset of MDD. METHODS: The presence of MDD, including age of onset, and of comorbid Axis I disorders were assessed in 396 depressed outpatients. RESULTS: Women were significantly more likely than men to meet criteria for comorbid bulimia nervosa and for simple phobia, while men were significantly more likely than women to meet criteria for lifetime history of alcohol abuse/dependence and other substance abuse/dependence. No other significant gender differences in those comorbid Axis I disorders examined were observed. In addition, the age of onset of the first episode of MDD was significantly lower in women than in men. CONCLUSIONS: Our findings are consistent with those of previous studies showing a greater prevalence of alcohol and substance abuse and dependence in men and of eating disorders in women.

Attention deficit hyperactivity disorder in childhood among adults with major depression.

The prevalence of attention deficit hyperactivity disorder (ADHD) with childhood onset and its relationship to course and treatment outcome of major depressive disorder (MDD) in adults was studied in 116 patients (ages 18-65) consecutively enrolled for treatment of MDD. Sixteen percent of the patient were found to meet full or subthreshold criteria for the DSM-III-R diagnosis of childhood ADHD. Twelve percent endorsed persistence of ADHD symptoms into adulthood. Depressed adults meeting criteria for childhood ADHD did not differ significantly from other depressed adults on any measures related to the chronicity or severity of the mood disorder, Axis I comorbidity, or response to acute antidepressant treatment. Our results are clinically important as they suggest that clinicians need to be aware of the possibility that a substantial proportion of patients with MDD may suffer from comorbid ADHD and that treatments need to include the targeting of possible residual ADHD symptoms in addition to those of depression.

Relapse in patients on long-term fluoxetine treatment: response to increased fluoxetine dose.

BACKGROUND: Although several studies have examined the long-term efficacy of antidepressants, relatively little attention has been paid to the management of relapses or recurrences during continued antidepressant treatment. This study examined whether depressed patients who had recovered and then relapsed on fluoxetine 20 mg/day would benefit from an increase in fluoxetine dose. METHOD: Eighteen patients who relapsed on fluoxetine 20 mg/day during long-term treatment with fluoxetine as part of a placebo-controlled study had their fluoxetine dose raised to 40 mg/day and were followed for at least 1 month (mean time = 4.7 months). RESULTS: Twelve (67%) were full responders, 3 (17%) partial responders, and 3 (17%) dropped out because of side effects (e.g., insomnia and agitation). Of those patients who had either full or partial response (N = 15; 83%), 3 complete responders had a recurrence on 40 mg/day after a mean of 5.8 months and 1 partial responder had a recurrence 11 months later. Overall, 11 (61%) of 18 patients maintained their response during their follow-up while taking the higher dose of fluoxetine. CONCLUSION: An increase in dose of fluoxetine to 40 mg/day appears to be an effective strategy in the treatment of relapse among depressed patients who had initially responded to fluoxetine 20 mg/day.

Personality disorder comorbidity with major depression and response to fluoxetine treatment.

The relationship between depression and comorbid personality disorders is still poorly understood. The aims of this study were to examine differences in depression severity between depressed outpatients with and without comorbid personality disorders, to determine the effect of a fixed dose of fluoxetine on personality disorders, and to assess the predictive value of personality disorder diagnoses at baseline with regard to response to fluoxetine. Eighty-three outpatients with major depressive disorder (MDD) were assessed with a self-rating scale, the Personality Diagnostic Questionnaire-Revised (PDQ-R), before and after 8 weeks of treatment with fluoxetine 20 mg/day. The presence of a cluster B diagnosis before treatment predicted positive outcome as measured by the change in score on the modified 17-item Hamilton Rating Scale for Depression (HAM-D-17*). Following treatment, we found significant reductions in the frequency of most individual personality disorder diagnoses and total PDQ-R score. While patients no longer meeting criteria for cluster B personality disorders after treatment had similar reductions in depressive symptoms compared to those maintaining the diagnoses, subjects no longer meeting criteria for cluster A and cluster C diagnoses after treatment exhibited significantly greater decreases in depression severity than those who maintained the diagnoses. Overall, these results suggest that fluoxetine may be beneficial in the treatment of certain personality disorder traits in patients with MDD.

Integrating cognitive therapy and pharmacotherapy in the treatment and prophylaxis of depression: a novel approach.

Psychiatric clinicians frequently prescribe biologic treatments such as antidepressant medication in combination with psychologic treatments such as psychotherapy. In the present article we propose a model integrating antidepressant treatment with Beck's cognitive therapy, a form of psychotherapy with established efficacy in the acute treatment of depression. We argue for adding cognitive therapy following successful pharmacological treatment, i.e., for spending cognitive therapy resources in the continuation phase of treatment, where they are most likely to make a unique and separate contribution to patient well-being, particularly in the areas of relapse prevention and treating residual symptoms. We encourage researchers to compare this treatment strategy to other approaches in terms of its ability to (1) prevent relapses and recurrences of depressive episodes, and (2) to impact positively on the overall quality of life in recovered depressed patients.

Dysfunctional attitudes in major depression. Changes with pharmacotherapy.

High levels of dysfunctional attitudes have been associated with greater severity of depression and poorer response to pharmacological treatment. The goal of our study was to examine this relationship and the changes in dysfunctional attitudes after treatment with fluoxetine, a relatively selective serotonin uptake inhibitor. Dysfunctional attitudes were evaluated with both the Cognitions Questionnaire (CQ) and the Dysfunctional Attitudes Scale (DAS) in 115 outpatients diagnosed as having major depressive disorder. After 8 weeks of treatment with fluoxetine, 67 of these patients again completed the DAS and the CQ. Dysfunctional attitudes were associated with depression severity both before and after treatment and decreased linearly with treatment of the depression. Negative thinking and dysfunctional attitudes, as measured by both DAS and CQ, were not predictive of the degree of improvement in depressive symptoms. These findings partly support a state-dependent interpretation of dysfunctional attitudes, and provide evidence of significant reductions in these attitudes after treatment with a serotonin uptake inhibitor.

Anger attacks in unipolar depression, Part 2: Neuroendocrine correlates and changes following fluoxetine treatment.

OBJECTIVE: Neuroendocrine derangements have been reported in both depression and aggressive behavior. The purpose of this study was to evaluate whether the subset of depressed patients with anger attacks have a distinctive neuroendocrine abnormality. METHOD: The thyrotropin-releasing hormone (TRH) test was administered to 25 patients with major depression, 12 of whom reported having anger attacks, at the Depression Research Program of the Clinical Psychopharmacology Unit at the Massachusetts General Hospital. Twenty-two subjects underwent the TRH test again after 8 weeks of treatment with fluoxetine, a relatively selective serotonin uptake inhibitor. RESULTS: The depressed patients with anger attacks had a blunted prolactin response to TRH stimulation compared to the depressed patients without anger attacks. Treatment with fluoxetine was followed by an overall increase in the prolactin response to TRH among the depressed patients with anger attacks. The prolactin response to TRH also tended to predict the degree of response to treatment. CONCLUSIONS: These results suggest that the subset of depressed patients with anger attacks may have a greater central serotonergic dysregulation than depressed patients without such attacks.

Anger attacks in unipolar depression, Part 1: Clinical correlates and response to fluoxetine treatment.

OBJECTIVE: Anger attacks are sudden, intense spells of anger associated with a surge of autonomic arousal including such symptoms as tachycardia, sweating, flushing, and a feeling of being out of control. The purpose of this study was to determine whether depressed patients with and without anger attacks exhibit distinct psychological characteristics and whether these attacks respond to treatment with fluoxetine. METHOD: The Anger Attacks Questionnaire, the Hamilton Rating Scale for Depression, the Symptom Questionnaire, and the Cook-Medley Hostility Scale were among the scales administered at the Depression Research Program of the Clinical Psychopharmacology Unit at the Massachusetts General Hospital to 127 medication-free outpatients with major depression and to 85 of these patients after 8 weeks of open treatment with a fixed dose (20 mg/day) of fluoxetine. RESULTS: At baseline, 44% of the depressed outpatients reported having anger attacks; these patients had significantly higher scores on measures of anxiety, somatization, and state and trait hostility than did the subjects who did not exhibit such attacks. After treatment, there were significant reductions in these measures, and the anger attacks disappeared in the majority (71%) of the patients who had previously reported them. There was a trend toward greater overall clinical improvement for patients with anger attacks than for patients without them. CONCLUSIONS: This study identified a subgroup of highly irritable and hostile depressed patients who report the presence of anger attacks and have a psychological profile distinct from that of depressed patients without anger attacks. Furthermore, fluoxetine treatment appears to be beneficial in reducing anger and hostility in these patients.