Anxiety Disorders: Fava M

Fava M. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · J Psychopharmacol. · Pubmed #16644769 No free full text.

Abstract: Despite the efficacy of currently available antidepressant treatment, residual symptoms are common among individuals treated for major depressive disorder and are associated with an increased risk of relapse and poor psychosocial functioning. However, distinguishing treatment-emergent side effects from residual symptoms can be challenging for clinicians. Anxiety, sleep disturbance, somnolence/fatigue, apathy and cognitive dysfunction are among the more frequent residual symptoms. Approaches to the management of residual symptoms include addressing treatment-emergent side effects and co-morbid conditions, optimizing antidepressant dosing and using augmentation therapy. Clinicians are often guided in their decisions by anecdotal impressions. Studies assessing the evaluation and treatment of residual symptoms and side effects will contribute importantly to the optimal acute and long-term management of depression.

Papakostas GI, Ongür D, Iosifescu DV, Mischoulon D, Fava M. · Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, 15 Parkman Street, WACC #812, Boston, MA 02114, USA. · Eur Neuropsychopharmacol. · Pubmed #15013029 No free full text.

Abstract: Cholesterol plays an integral role in the structure and function of the cell membrane and may also affect neurotransmission in the central nervous system. Previous work has identified abnormalities in serum cholesterol levels in patients with mood and anxiety disorders as well as in suicidal patients. However, the biological significance of these abnormalities remains to be clarified. An understanding of how serum cholesterol relates to the pathophysiology of mood disorders may generate biological markers that predict treatment response as well as targets for novel therapeutic strategies. In this article, we review the literature studying the significance of cholesterol in mood and anxiety disorders, with an emphasis on new studies focusing on the adverse impact of hypercholesterolemia on the treatment of major depressive disorder (MDD). We then propose possible mechanisms that would account for the relationship between elevated cholesterol and treatment non-response in MDD.

Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, Norquist G, Howland RH, Lebowitz B, McGrath PJ, Shores-Wilson K, Biggs MM, Balasubramani GK, Fava M, Anonymous00109. · Department of Psychiatry, University of Texas Southwestern Medical Center, Exchange Park Express, American General Tower, 6363 Forest Park Rd., Suite 1300, Dallas, TX 75390-9119, USA. · Am J Psychiatry. · Pubmed #16390886 links to  free full text

Abstract: OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in "real world" patients are not established. The authors' primary objectives in this study were to evaluate the effectiveness of citalopram, an SSRI, using measurement-based care in actual practice, and to identify predictors of symptom remission in outpatients with major depressive disorder. METHOD: This clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care "real world" settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. The clinicians were assisted by a clinical research coordinator in the application of measurement-based care, which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures. Remission was defined as an exit score of <or=7 on the 17-item Hamilton Depression Rating Scale (HAM-D) (primary outcome) or a score of <or=5 on the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) (secondary outcome). Response was defined as a reduction of >or=50% in baseline QIDS-SR score. RESULTS: Nearly 80% of the 2,876 outpatients in the analyzed sample had chronic or recurrent major depression; most also had a number of comorbid general medical and psychiatric conditions. The mean exit citalopram dose was 41.8 mg/day. Remission rates were 28% (HAM-D) and 33% (QIDS-SR). The response rate was 47% (QIDS-SR). Patients in primary and psychiatric care settings did not differ in remission or response rates. A substantial portion of participants who achieved either response or remission at study exit did so at or after 8 weeks of treatment. Participants who were Caucasian, female, employed, or had higher levels of education or income had higher HAM-D remission rates; longer index episodes, more concurrent psychiatric disorders (especially anxiety disorders or drug abuse), more general medical disorders, and lower baseline function and quality of life were associated with lower HAM-D remission rates. CONCLUSIONS: The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials. The systematic use of easily implemented measurement-based care procedures may have assisted in achieving these results.

Farabaugh A, Mischoulon D, Fava M, Wu SL, Mascarini A, Tossani E, Alpert JE. · Depression Clinical and Research Program, Massachusetts General Hospital, MA WAC 812, USA. · Int Clin Psychopharmacol. · Pubmed #15729083 No free full text.

Abstract: The 17-item Hamilton Rating Scale for Depression (HAMD-17) Anxiety/Somatization factor includes six items: Anxiety (psychic), Anxiety (somatic), Somatic Symptoms (gastrointestinal), Somatic Symptoms (general), Hypochondriasis and Insight. This study examines the relationship between early changes (defined as those observed between baseline and week 1) in these HAMD-17 Anxiety/Somatization Factor items and treatment outcome among major depressive disorder (MDD) patients who participated in a study comparing the antidepressant efficacy of a standardized extract of hypericum with both placebo and fluoxetine. Following a 1-week, single-blind washout, patients with MDD diagnosed by the Structured Clinical Interview for DSM-IV (SCID) were randomized to 12 weeks of double-blind treatment with hypericum extract (900 mg/day), fluoxetine (20 mg/day) or placebo. The relationship between early changes in HAMD-17 anxiety/somatization factor items and treatment outcome was assessed separately for patients who received study treatment (hypericum or fluoxetine) versus placebo with a logistic regression method. One hundred and thirty-five patients (female 57%, mean age=37.3+/-11.0 years; mean baseline HAMD-17=19.7+/-3.2 years) were randomized to double-blind treatment and were included in the intent-to-treat (ITT) analyses. After adjusting for baseline HAMD-17 scores and for multiple comparisons with the Bonferroni correction, patients who remitted (HAMD-17 score <8) after study treatment had significantly greater early improvement in Somatic Symptoms (General) scores than non-remitters. No other significant differences in early changes were noted for the remaining items between remitters versus non-remitters who received active treatment. For patients treated with placebo, early change was not predictive of remission for any of the items after Bonferroni correction. In conclusion, the presence of early improvement on the HAMD-17 item concerning fatigue and general somatic symptoms is significantly predictive of achieving remission at endpoint with active study treatment but not with placebo.

Fava M, Alpert JE, Carmin CN, Wisniewski SR, Trivedi MH, Biggs MM, Shores-Wilson K, Morgan D, Schwartz T, Balasubramani GK, Rush AJ. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · Psychol Med. · Pubmed #15697056 No free full text.

Abstract: BACKGROUND: Anxious depression, defined as Major Depressive Disorder (MDD) with high levels of anxiety symptoms, may represent a relatively common depressive subtype, with distinctive features. OBJECTIVE: The objective of this study was to determine the prevalence of anxious depression and to define its clinical correlates and symptom patterns. METHOD: Baseline clinical and sociodemographic data were collected on 1450 subjects participating in the STAR*D study. A baseline Hamilton Rating Scale for Depression (HAM-D) Anxiety/ Somatization factor score of > or =7 was considered indicative of anxious depression. The types and degree of concurrent psychiatric symptoms were measured using the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items endorsed by study participants for each diagnostic category. MDD symptoms were assessed by clinical telephone interview with the 30-item Inventory of Depressive Symptomatology (IDS-C30). RESULTS: The prevalence of anxious depression in this population was 46 %. Patients with anxious MDD were significantly more likely to be older, unemployed, less educated, more severely depressed, and to have suicidal ideation before and after adjustment for severity of depression. As far as concurrent psychiatric symptoms are concerned, patients with anxious depression were significantly more likely to endorse symptoms related to generalized anxiety, obsessive compulsive, panic, post-traumatic stress, agoraphobia, hypochondriasis, and somatoform disorders before and after adjustment for severity of depression. Anxious-depression individuals were also significantly less likely to endorse IDS-C30 items concerning atypical features, and were significantly more likely to endorse items concerning melancholic/endogenous depression features. CONCLUSION: This study supports specific clinical and sociodemographic correlates of MDD associated with high levels of anxiety (anxious depression).

Alpert JE, Franznick DA, Hollander SB, Fava M. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston 02114, USA. · J Clin Psychiatry. · Pubmed #15323591 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and tolerability of gepirone extended-release (ER) tablets in patients with major depressive disorder (MDD) and high ratings of anxiety (anxious depression). METHOD: This subgroup analysis was derived from an 8-week, double-blind, placebo-controlled study of gepirone ER in patients with MDD. Male and female patients 18 to 69 years of age who met DSM-IV criteria for MDD and had high ratings of anxiety (Hamilton Rating Scale for Depression [HAM-D-17] total score > or = 20 and HAM-D-17 factor I [anxiety/somatization] score > 6) were included in this subgroup analysis. Eligible patients with anxious depression were randomly assigned to receive either placebo or gepirone ER, 20 mg to 80 mg daily. Patient assessments were performed at weeks 1, 2, 3, 4, 6, and 8. Treatment efficacy was evaluated by mean HAM-D-17 total scores and mean changes from baseline in (1) HAM-D-17 total scores, (2) HAM-D-17 factor I (anxiety/somatization) scores, and (3) HAM-D-17 item 12 (anxiety, psychic) scores. All statistical tests were 2-sided and considered statistically significant if the p value was <.05. Between-group comparisons were analyzed using least-squares analysis of variance on the change from baseline at each visit with the last observation carried forward (LOCF). The Cochran-Mantel-Haenszel test adjusting for center was also performed on the percentage of patients in each treatment group at each visit (LOCF) who met the response criterion on the HAM-D-17 (> or = 50% decrease from baseline) or remission criterion (HAM-D-17 total score < or = 7). RESULTS: Gepirone ER-treated patients (N = 58) experienced a statistically significant (p <.05) reduction in mean HAM-D-17 total score at week 3, 6, and 8 compared with placebo-treated patients (N = 75). A statistically significant effect (p <.05) in favor of gepirone ER was observed in mean change from baseline in HAM-D-17 total scores and for HAM-D factor I (anxiety/somatization) scores from week 2 onward. A statistically significant (p < or =.01) effect in favor of gepirone ER was observed in HAM-D-17 item 12 (anxiety, psychic) scores throughout the 8-week trial. There were significantly more patients in the gepirone ER group compared with the placebo group who were HAM-D-17 responders (p <.05) at endpoint and who met the criteria for HAM-D-17 remission at week 3 (p <.05) and weeks 6 and 8 (p <.01). Overall, gepirone ER was well tolerated, with rates of weight gain and sexual dysfunction comparable to placebo. Adverse events were generally mild to moderate. The most commonly reported adverse events were dizziness and nausea. CONCLUSIONS: Gepirone ER is an effective and well-tolerated treatment for patients with anxious depression.

Cassano P, Soares CN, Cohen LS, Lyster AK, Fava M. · Depression Clinical and Research Program, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, MA 02114, U.S.A. · Arch Womens Ment Health. · Pubmed #15241662 No free full text.

Abstract: OBJECTIVE: To examine sex- and age-related differences of treatment outcome in a cohort of outpatients with major depressive disorder (MDD), with and without comorbid anxiety, treated with fluoxetine. METHODS: Outpatients with a SCID-diagnosis of MDD aged 18 to 65 years were treated openly with fluoxetine (20 mg/day) for 8 weeks. The 17-item Hamilton Depression Rating Scale (HAM-D-17) was administered at baseline, and at weeks 2, 4, 6 and 8. Remission of MDD was defined as a HAM-D-17 score < or =7 at week 8. Rates of remission and change of depressive symptoms of MDD were compared among women aged < 45 years and > or =45 years. The analyses were then repeated in men. The presence of comorbid anxiety disorders was included in the prediction model for change of depressive symptoms of MDD across age and sex. RESULTS: 176 women and 153 men were included in this analysis. Remission of MDD occurred in 57.1% and 50% of younger and older women respectively. Similar rates were present in men (57.2% and 49.1%, respectively). Age did not predict remission of depression or change of depressive symptoms of MDD, in both women and men. Anxious and non-anxious subtypes of depression did not present sex- or age-related differences in treatment outcome. CONCLUSION: In this cohort of outpatients with MDD, we observed no sex- or age-related differences in response to an 8-week treatment with the SSRI fluoxetine. Similarly, there were no age-related differences among women with anxious and non-anxious subtype of depression.

Joliat MJ, Schmidt ME, Fava M, Zhang S, Michelson D, Trapp NJ, Miner CM. · Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA. · J Clin Psychiatry. · Pubmed #15096077 No free full text.

Abstract: BACKGROUND: Severity of anxiety does not appear to influence the antidepressant response to fluoxetine during acute treatment of major depressive disorder (MDD). We report a retrospective pooled analysis of 2 studies to assess the effect of associated anxiety on the efficacy of fluoxetine in the continuation treatment phase of MDD. METHOD: Patients whose MDD remitted (study 1) or responded (study 2) after approximately 12 to 13 weeks of open-label treatment with fluoxetine 20 mg daily were randomly assigned in double-blind fashion to placebo, continued treatment with fluoxetine 20 mg daily, or, in study 2 only, treatment with enteric-coated fluoxetine 90 mg once weekly, for at least 25 weeks. Both studies included male and female outpatients who met criteria for MDD as assessed by DSM-III-R (study 1) or DSM-IV (study 2). Patients were categorized into high anxiety (> or = 7) or low anxiety (< 7) subgroups based on baseline Hamilton Rating Scale for Depression (HAM-D) anxiety/somatization subfactor scores. Subgroups were compared by therapy for time from randomization to relapse and change in efficacy scores. RESULTS: No significant differences in time to relapse were observed between anxiety subgroups in either active treatment group. However, in patients switched to placebo for continuation treatment, the high anxiety subgroup had a significantly higher risk of relapse than those with low anxiety (risk ratio = 1.63, p =.013). Significant differences between anxiety groups were seen in change in HAM-D anxiety/somatization subfactor scores in the fluoxetine 20 mg and placebo treatment groups, and in change in HAM-D-17 scores in the placebo treatment group (p <.05). CONCLUSION: Although high baseline anxiety does not appear to impact the benefit of continuation therapy with fluoxetine, it does appear to predict increased risk of relapse in individuals who do not remain on antidepressant therapy for the duration of continuation treatment.

Sonawalla SB, Spillmann MK, Kolsky AR, Alpert JE, Nierenberg AA, Rosenbaum JF, Fava M. · Depression Clinical and Research Program, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA. · J Clin Psychiatry. · Pubmed #10520975 No free full text.

Abstract: BACKGROUND: Major depression with comorbid anxiety disorder is associated with poor antidepressant outcome compared with major depression without comorbid anxiety disorder. The purpose of our study was to assess changes in depressive symptoms and anxiety levels in outpatients with major depression with comorbid anxiety disorder following 12 weeks of open treatment with fluvoxamine. METHOD: We enrolled 30 outpatients (mean +/- SD age = 39.4 +/- 11.3 years; 16 women and 14 men) with DSM-IV major depressive disorder accompanied by one or more current comorbid DSM-IV anxiety disorders in our study. Patients were treated openly with fluvoxamine initiated at 50 mg/day, with an upward titration to a maximum of 200 mg/day (mean +/- SD dose = 143 +/- 45 mg/day). Efficacy assessments included the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and Clinical Global Impressions-Severity of Illness (CGI-S) and Improvement (CGI-I) scales for both depression and anxiety. Intent-to-treat analysis was used to assess outcome. RESULTS: The mean +/- SD number of comorbid anxiety disorders per patient was 2.1 +/- 1.1. Following fluvoxamine treatment, the mean +/- SD HAM-D-17 score dropped from 20.2 +/- 3.3 to 1 1.0 +/- 7.0 (p < .0001). The mean +/- SD depression CGI-S score dropped from 4.0 +/- 0.6 to 2.4 +/- 1.1 (p < .0001), and the mean +/- SD anxiety CGI-S score decreased from 4.1 +/- 0.8 to 2.5 +/- 1.2 (p < .0001). Eighteen (60%) of the 30 patients had CGI-I scores < or = 2 for both anxiety and depression at endpoint, with 53% showing a > or = 50% reduction in HAM-D-17 scores at endpoint. CONCLUSION: Although preliminary, our findings suggest that fluvoxamine is effective in treating outpatients with major depression with comorbid anxiety disorder, having a significant effect on both depression and anxiety symptoms. Further double-blind, placebo-controlled trials are needed, in a larger sample, to confirm our findings.

Fava M, Asnis GM, Shrivastava R, Lydiard B, Bastani B, Sheehan D, Roth T. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114-2696, USA. · J Clin Psychopharmacol. · Pubmed #19440075 No free full text.

Abstract: A multicenter, double-blind, parallel-group study was designed to assess the efficacy and safety of zolpidem extended-release coadministered with escitalopram in patients with insomnia and comorbid generalized anxiety disorder. Patients (N = 383) received open-label escitalopram 10 mg/d and were randomized to either adjunct zolpidem extended-release 12.5 mg or placebo. The primary efficacy measure was change from baseline to week 8 in subjective total sleep time. Secondary efficacy measures included subjective sleep onset latency, number of awakenings, wake time after sleep onset, sleep quality, the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, the Sleep Impact Scale, the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire, and the Sheehan Disability Scale. The last-observation-carried-forward method was used to impute missing values for most efficacy measures. Safety was monitored at each visit. At week 8 and all time points, there was a significant improvement in the zolpidem extended-release/escitalopram group compared with placebo/escitalopram for total sleep time (P < 0.0001). Most of the secondary efficacy measures also significantly favored zolpidem at most visits (P < 0.0001). The most common treatment-emergent adverse events in both groups were nausea, dizziness, headache, fatigue, and dry mouth. Concurrent zolpidem extended-release/escitalopram, compared with placebo/escitalopram, significantly improved insomnia and sleep-related next-day symptoms, but not anxiety symptoms, in patients with comorbid insomnia and generalized anxiety disorder.

Fava M, Iosifescu DV, Pedrelli P, Baer L. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · Psychother Psychosom. · Pubmed #19218827 No free full text.

Abstract: BACKGROUND: We have recently developed the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ), a brief scale to measure cognitive and executive dysfunction in mood and anxiety disorders, and we here report on its reliability and validity. METHODS: The internal consistency of the CPFQ was assessed by computing Cronbach's coefficient alpha based upon the average intercorrelation of the 7 items of the CPFQ in a sample of depressed outpatients and by factor analyzing data from the same sample to confirm that the scale is unifactorial and measuring a single construct. Test-retest reliability of the CPFQ was assessed in a different sample of depressed outpatients by computing Pearson's correlation coefficient between pretreatment screening scores and pretreatment baseline scores. Sensitivity to change of the CPFQ was assessed by computing the dependent t test for the subjects in the active treatment condition in the second sample of depressed outpatients. Finally, convergent validity for the CPFQ was assessed in two different ways. RESULTS: We found that the CPFQ is a unifactorial scale, with strong internal consistency. It has good temporal stability as indicated by high test-retest reliability. The CPFQ was also found to be sensitive to change with treatment and displayed convergent validity by significant correlations with other measures of sleepiness, fatigue, apathy and neuropsychological functioning. Although, as expected, the CPFQ was significantly correlated with a measure of depression, the moderate correlation (r approximately 0.30) indicates that the CPFQ is measuring a different construct. CONCLUSION: In summary, the CPFQ is a unifactorial scale, with strong internal consistency, good temporal stability and sensitivity to change with treatment. Further studies will be needed to assess the validity and reliability of this instrument in other psychiatric and neuropsychiatric conditions associated with cognitive dysfunction.

Perlis RH, Fava M, Trivedi MH, Alpert J, Luther JF, Wisniewski SR, Rush AJ. · Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. · Acta Psychiatr Scand. · Pubmed #19207123 No free full text.

Abstract: OBJECTIVE: Irritability is common during major depressive episodes, but its clinical significance and overlap with symptoms of anxiety or bipolar disorder remains unclear. We examined clinical correlates of irritability in a confirmatory cohort of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study participants with major depressive disorder (MDD). METHOD: Logistic regression was used to identify features associated with presence of irritability on the clinician-rated Inventory of Depressive Symptomatology. RESULTS: Of 2307 study participants, 1067(46%) reported irritability at least half the time during the preceding week; they were more likely to be female, to be younger, to experience greater depression severity and anxiety, and to report poorer quality of life, prior suicide attempts and suicidal ideation. Bipolar spectrum features were not more common among those with irritability. CONCLUSION: Irritable depression is not a distinct subtype of MDD, but irritability is associated with greater overall severity, anxiety comorbidity and suicidality.

Trivedi MH, Thase ME, Fava M, Nelson CJ, Yang H, Qi Y, Tran QV, Pikalov A, Carlson BX, Marcus RN, Berman RM. · UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9119, USA. · J Clin Psychiatry. · Pubmed #19192475 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy of adjunctive aripiprazole to standard antidepressant therapy (ADT) for patients with DSM-IV major depressive disorder with anxious/atypical features at baseline. METHOD: Data from 2 identical 14-week studies (an 8-week prospective ADT treatment phase and a 6-week randomized, double-blind phase) of aripiprazole augmentation were pooled to evaluate efficacy and safety in the 2 subgroups. The primary efficacy endpoint was mean change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from end of ADT treatment to end of randomized treatment (last observation carried forward). Anxious depression was defined by a Hamilton Rating Scale for Depression anxiety/somatization factor score > or = 7, and atypical depression was defined by previously described criteria on the Inventory of Depressive Symptomatology-Self-Report. Both anxious and atypical subtypes were defined based on symptoms at entry into prospective ADT (week 0). Patients were enrolled between June 2004 and April 2006 in one study and from September 2004 to December 2006 in the other (total randomized population, N = 742; anxious/nonanxious population, N = 740; atypical/nonatypical population, N = 737). RESULTS: Completion rates were between 84% and 90% and comparable across all subgroups, with low discontinuations due to adverse events. Patients receiving adjunctive aripiprazole demonstrated significantly greater improvement in MADRS total score versus patients receiving adjunctive placebo, starting at week 1 or week 2 and continuing through to endpoint (anxious: -8.72 vs. -6.17, p < or = .001; nonanxious: -8.61 vs. -4.97, p < or = .001; atypical: -9.31 vs. -5.15, p < or = .001; nonatypical: -8.08 vs. -6.22, p < .05). At endpoint, remission rates were also significantly higher with adjunctive aripiprazole versus adjunctive placebo (p < .05) in all subgroups. Treatment emergent adverse event profile was similar in all subgroups and comparable to the total population. Reporting of akathisia and weight gain on aripiprazole treatment did not differ between subgroups. CONCLUSION: Adjunctive aripiprazole is an effective treatment for patients with major depression presenting with either anxious or atypical features. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00095823 and NCT00095758.

Husain MM, Rush JA, Wisniewski SR, McClintock SM, Fava M, Nierenberg AA, Davis L, Balasubramani GK, Young E, Albala AA, Trivedi MH. · Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX 75390-8898, USA. · J Clin Psychiatry. · Pubmed #19192454 No free full text.

Abstract: OBJECTIVE: It is unclear whether a positive family history of depression affects the clinical presentation or effectiveness of treatment for major depressive disorder (MDD). We aimed to determine whether depressed patients with a positive family history of depression differed from those without in terms of baseline sociodemographic and clinical characteristics, including concurrent comorbid conditions and treatment outcome with citalopram in a large, multicenter effectiveness trial. METHOD: Clinical outcome and sociodemographic information were collected on 2876 participants with DSM-IV MDD enrolled from July 2001 through April 2004 in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Participants with and without a family history of depression, as determined by self-report at initial assessment, were compared. RESULTS: Over half (55.6%) (1585/2853) of the evaluable sample reported a positive family history of depression. A positive family history of depression was associated with an earlier age at onset of MDD, a longer length of illness, and more comorbid generalized anxiety disorder and prior suicide attempts. These participants had a slightly faster onset of remission, and slightly greater side effect burden, but they did not differ overall in response or remission rates. CONCLUSIONS: A family history of depression was associated with several clinical characteristics, although its usefulness as a predictor of treatment outcome is questionable. The slightly faster remission with an SSRI despite the slightly greater side effect burden indicates the effectiveness of using an SSRI in treating depressed patients both with and without a family history of depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00021528.

Howland RH, Wilson MG, Kornstein SG, Clayton AH, Trivedi MH, Wohlreich MM, Fava M. · Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA. · Ann Clin Psychiatry. · Pubmed #19034753 No free full text.

Abstract: BACKGROUND: To identify putative demographic and clinical variables that correlate with antidepressant response to the SNRI duloxetine in major depression. METHODS: The effect of 130 candidate treatment outcome predictors was examined on 3 dependent treatment outcome measures related to depression: 1) depression symptom outcome measured by HAMD-17 total and HAMD-17 percent change from baseline to endpoint, 2) remission (HAMD-17 < or = 7 at endpoint) and response (> or = 50% reduction in HAMD-17 from baseline to endpoint) rates, and 3) time to response (days to > or = 50% reduction in HAMD-17). RESULTS: Eleven variables had an overall predictive index of > or = 20% and were associated with poorer treatment outcome: HAMD-17 total, duration of current MDD episode, leaden paralysis, fatigue, HAMA total, HAMA items 2 and 8, HAMD-17 anxiety/somatization subscale, anxiety-related comorbid conditions, and VAS overall pain and pain while awake. CONCLUSIONS: Our results highlight the clinical relevance of more severe and/or persistent levels of depression, psychiatric and medical comorbidity, and symptoms characteristic of atypical depression (leaden paralysis and fatigue) and confirm findings from other studies that such patients may respond less well or take longer to respond to pharmacotherapy. Consistent with previous SNRI studies, we found no significant association between age, gender, and race/ethnicity and treatment outcome.

Evins AE, Culhane MA, Alpert JE, Pava J, Liese BS, Farabaugh A, Fava M. · Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · J Clin Psychopharmacol. · Pubmed #19011435 No free full text.

Abstract: Although there is a strong relationship between depression and smoking, most nicotine dependence treatment trials exclude depressed smokers. Our objective was to determine whether bupropion improves abstinence rates and abstinence-associated depressive symptoms when added to transdermal nicotine replacement therapy (NRT) and group cognitive behavioral therapy (CBT) in smokers with unipolar depressive disorder (UDD). Adult smokers with current (n = 90) or past (n = 109) UDD were randomly assigned to receive bupropion or placebo added to NRT and CBT for 13 weeks. In the primary analysis, with dropouts considered smokers, 36% (35/97) of those on bupropion and 31% (32/102) on placebo attained biochemically validated 7-day point prevalence abstinence at end of treatment (not significant). Because of a high dropout rate (50%) and a significant difference in abstinence status at dropout by treatment group, a traditional intent-to-treat analysis with last observation carried forward imputation of abstinence status was performed. In this secondary analysis, 56% (54/97) of those on bupropion and 41% (42/102) on placebo met criteria for abstinence at end of trial, chi2 = 4.18, P = 0.04. Nicotine replacement therapy usage and absence of a comorbid anxiety disorder predicted abstinence. Abstinence was associated with increased depressive symptoms, regardless of bupropion treatment. Thus, in the primary analysis, bupropion neither increased the efficacy of intensive group CBT and NRT for smoking cessation in smokers with UDD nor prevented abstinence-associated depressive symptoms. Bupropion seemed to provide an advantage for smoking cessation for those who remained in the trial. The dropout rate was high and was characterized by a higher prevalence of current comorbid anxiety disorder. Given the high abstinence rate achieved with CBT plus NRT, a ceiling effect related to the high level of intervention received by all subjects may have prevented an adequate test of bupropion.

Howland RH, Rush AJ, Wisniewski SR, Trivedi MH, Warden D, Fava M, Davis LL, Balasubramani GK, McGrath PJ, Berman SR. · Department of Psychiatry, University of Pittsburgh Medical Center, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213, United States. · Drug Alcohol Depend. · Pubmed #18986774 No free full text.

Abstract: BACKGROUND: Depressed patients often present with comorbid anxiety and/or substance use disorder. This report compares the four groups defined by the disorders (anxiety disorder, substance use disorder, both, and neither) in terms of baseline clinical and sociodemographic features, and in terms of outcomes following treatment with citalopram (a selective serotonin reuptake inhibitor). METHODS: The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial enrolled 2838 outpatients with non-psychotic major depressive disorder (MDD) from 18 primary and 23 psychiatric care clinics. Clinical and sociodemographic features were assessed at baseline. These baseline features and the treatment outcomes following treatment with citalopram were compared among the four groups. RESULTS: Participants with non-psychotic MDD and comorbid anxiety and/or substance use disorder showed several distinctive baseline sociodemographic and clinical features. They also showed greater depression severity; length of illness; likelihood of anxious, atypical or melancholic features; more intolerance/attrition; and worse remission/response outcomes with treatment. Participants with either anxiety or substance use disorder showed outcomes generally intermediate between those with both and those with neither. CONCLUSIONS: Comorbid anxiety and/or substance use disorder are clinically identifiable, and their presence may define distinct MDD subgroups that have more problems and worse pharmacological treatment outcomes. They may benefit from more aggressive, multi-faceted treatment and psychosocial rehabilitation targeted at reducing their psychological comorbidity and functional impairment.

Papakostas GI, McGrath P, Stewart J, Charles D, Chen Y, Mischoulon D, Dording C, Fava M. · Depression Clinical and Research Program at Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · Psychiatry Res. · Pubmed #18755514 No free full text.

Abstract: The purpose of this study was to examine whether the presence/severity of psychic and somatic anxiety symptoms predicted clinical response following a 12-week, flexible-dose (20-60 mg daily), open-label trial of fluoxetine for major depressive disorder (MDD). The presence and severity of psychic and somatic anxiety symptoms were assessed with the use of select subscales of the Symptom Questionnaire and the Hopkins Symptom Checklist among 518 outpatients with MDD. With the use of separate logistic regressions, we tested for the relationship between clinical response, baseline Hamilton Depression Rating Scale (HAM-D-17) scores, and subscale scores at baseline entered separately as independent variables Overall completion, response and remission rates for the trial were 64.2%, 55.4%, and 48.9%, respectively. All subscale scores selected for this analysis significantly predicted treatment response to fluoxetine. The presence/severity of psychic and somatic anxiety symptoms of MDD at baseline predicted an increased likelihood of non-response to fluoxetine in MDD. Studies examining whether specific treatment strategies are more effective than the selective serotonin reuptake inhibitors for MDD patients with high levels of co-morbid psychic and somatic anxiety symptoms are warranted.

Rush AJ, Wisniewski SR, Warden D, Luther JF, Davis LL, Fava M, Nierenberg AA, Trivedi MH. · Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. · Arch Gen Psychiatry. · Pubmed #18678792 links to  free full text

Abstract: CONTEXT: Little is known about selecting among second-step medications for major depressive disorder after intolerance or lack of remission with an initial selective serotonin reuptake inhibitor. OBJECTIVE: To determine whether sociodemographic, clinical, or first-step treatment features predict remission with or intolerance overall or differentially to any 1 of 3 second-step medications after an unsatisfactory outcome with citalopram hydrobromide. DESIGN: An equipoise stratified randomized study. Participants were recruited from July 17, 2001, through April 20, 2004. SETTING: Public or private sector primary care (n = 18) and psychiatric care (n = 23) settings across the United States. PARTICIPANTS: Representative outpatients aged 18 to 75 years with nonpsychotic major depressive disorder (N = 727). INTERVENTIONS: Sustained-release bupropion hydrochloride was started at 150 mg/d and incrementally increased to 400 mg/d. Sertraline hydrochloride was started at 50 mg/d and incrementally increased to 200 mg/d. Extended-release venlafaxine hydrochloride was started at 37.5 mg/d and incrementally increased to 375 mg/d. MAIN OUTCOME MEASURES: The 16-item Quick Inventory of Depressive Symptomatology, Self-Rated and the Frequency, Intensity, and Burden of Side Effects Rating. RESULTS: Remission was more likely among participants who were white, employed, cohabiting or married, or privately insured or who had prior intolerance to citalopram or at least a response to citalopram, and no prior suicide attempts. Remission was less likely among participants with concurrent generalized anxiety, obsessive-compulsive, panic, or posttraumatic stress disorders; social phobia; anxious or melancholic features; or more severe depression. Intolerance was less likely for Hispanic participants, but more likely for participants with previous suicide attempts or intolerance to citalopram. Participants with concurrent substance use were less likely to remit (odds ratio, 0.37) and more likely not to tolerate extended-release venlafaxine. Intolerance to citalopram was associated with intolerance to sertraline (P = .04). CONCLUSIONS: Clinical, demographic, and treatment history were of little value in recommending 1 medication vs another as a second-step treatment for major depressive disorder. Participants most likely to remit in the second step had less Axis I psychiatric disorder comorbidity, less social disadvantage, and at least a response to citalopram in the first step. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00021528.

Papakostas GI, Stahl SM, Krishen A, Seifert CA, Tucker VL, Goodale EP, Fava M. · Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. · J Clin Psychiatry. · Pubmed #18605812 No free full text.

Abstract: OBJECTIVE: The goal of this work was to compare the efficacy of the norepinephrine and dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). METHOD: Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >or= 7. RESULTS: Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HAM-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean +/- SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. CONCLUSIONS: There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as 1 indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain 1 additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect such as anxiety.

Pizzagalli DA, Iosifescu D, Hallett LA, Ratner KG, Fava M. · Department of Psychology, Harvard University, 1220 William James Hall, 33 Kirkland Street, Cambridge, MA 02138, USA. · J Psychiatr Res. · Pubmed #18433774 No free full text.

Abstract: OBJECTIVE: Anhedonia, the lack of reactivity to pleasurable stimuli, is a cardinal feature of depression that has received renewed interest as a potential endophenotype of this debilitating disease. The goal of the present study was to test the hypothesis that individuals with major depression are characterized by blunted reward responsiveness, particularly when anhedonic symptoms are prominent. METHODS: A probabilistic reward task rooted within signal-detection theory was utilized to objectively assess hedonic capacity in 23 unmedicated subjects meeting DSM-IV criteria for major depressive disorder (MDD) and 25 matched control subjects recruited from the community. Hedonic capacity was defined as reward responsiveness - i.e., the participants' propensity to modulate behavior as a function of reward. RESULTS: Compared to controls, MDD subjects showed significantly reduced reward responsiveness. Trial-by-trial probability analyses revealed that MDD subjects, while responsive to delivery of single rewards, were impaired at integrating reinforcement history over time and expressing a response bias toward a more frequently rewarded cue in the absence of immediate reward. This selective impairment correlated with self-reported anhedonic symptoms, even after considering anxiety symptoms and general distress. CONCLUSIONS: These findings indicate that MDD is characterized by an impaired tendency to modulate behavior as a function of prior reinforcements, and provides initial clues about which aspects of hedonic processing might be dysfunctional in depression.

Fava M, Rush AJ, Alpert JE, Balasubramani GK, Wisniewski SR, Carmin CN, Biggs MM, Zisook S, Leuchter A, Howland R, Warden D, Trivedi MH. · Depression Clinical and Research Program, Massachusetts General Hospital, Boston, MA 02114, USA. · Am J Psychiatry. · Pubmed #18172020 links to  free full text

Abstract: OBJECTIVE: About half of outpatients with major depressive disorder also have clinically meaningful levels of anxiety. The authors conducted a secondary data analysis to compare antidepressant treatment outcomes for patients with anxious and nonanxious major depression in Levels 1 and 2 of the STAR*D study. METHOD: A total of 2,876 adult outpatients with major depressive disorder, enrolled from 18 primary and 23 psychiatric care sites, received citalopram in Level 1 of STAR*D. In Level 2, a total of 1,292 patients who did not remit with or tolerate citalopram were randomly assigned either to switch to sustained-release bupropion (N=239), sertraline (N=238), or extended-release venlafaxine (N=250) or to continue taking citalopram and receive augmentation with sustained-release bupropion (N=279) or buspirone (N=286). Treatment could last up to 14 weeks in each level. Patients were designated as having anxious depression if their anxiety/somatization factor score from the 17-item Hamilton Depression Rating Scale (HAM-D) was 7 or higher at baseline. Rates of remission and response as well as times to remission and response were compared between patients with anxious depression and those with nonanxious depression. RESULTS: In Level 1 of STAR*D, 53.2% of patients had anxious depression. Remission was significantly less likely and took longer to occur in these patients than in those with nonanxious depression. Ratings of side effect frequency, intensity, and burden, as well as the number of serious adverse events, were significantly greater in the anxious depression group. Similarly, in Level 2, patients with anxious depression fared significantly worse in both the switching and augmentation options. CONCLUSIONS: Anxious depression is associated with poorer acute outcomes than nonanxious depression following antidepressant treatment.

Davis LL, Frazier EC, Gaynes BN, Trivedi MH, Wisniewski SR, Fava M, Barkin J, Kashner TM, Shelton RC, Alpert JE, Rush AJ. · Department of Veterans Affairs (VA) Medical Center, Tuscaloosa, Ala. 35404, USA. · J Clin Psychiatry. · Pubmed #18162025 No free full text.

Abstract: OBJECTIVE: This report compares the baseline demographic and clinical characteristics of outpatients with nonpsychotic major depressive disorder (MDD) and a family history of substance use disorder (SUD) versus those with MDD and no family history of SUD. METHOD: Using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, we grouped participants with MDD (DSM-IV criteria) according to presence or absence of family history of SUD based on participant report. Between-group comparisons were made of demographic and clinical characteristics, depressive symptoms, and psychiatric co-morbidities. Patients were enrolled from July 2001 until August 2004. RESULTS: Of 4010 participants, 46% had a positive family history of SUD. Those with a positive family history were less likely to be Hispanic (p = .0029) and more likely to be female (p = .0013). They were less educated (p = .0120), less likely to be married (p < .01), and more likely to be divorced (p < .01). They also reported an earlier age at onset of MDD, greater length of illness, and more major depressive episodes (all p < .001). They had an increased likelihood of recurrent MDD, more prior suicide attempts, and more concurrent psychiatric comorbidities, including posttraumatic stress disorder, SUD, and generalized anxiety disorder (all p < .0001). CONCLUSION: Depressed patients with a family history of SUD had a more severe previous course of depression, were more likely to have attempted suicide, and had a greater burden of psychiatric comorbid conditions than patients without such a family history. These findings represent important clinical features to be considered in the evaluation and treatment planning of patients with MDD.

Young EA, Kornstein SG, Harvey AT, Wisniewski SR, Barkin J, Fava M, Trivedi MH, Rush AJ. · Department of Psychiatry and Molecular and Behavioral Neurosciences Institute, University of Michigan, MBNI, 205 Zina Pitcher place, Ann Arbor, MI 48109-0720, and Massachusetts General Hospital, Boston 02114, USA. · Psychoneuroendocrinology. · Pubmed #17629629 links to  free full text

Abstract: OBJECTIVE: Hormone-based contraceptives affect mood in healthy women or in women with premenstrual dysphoric disorder (PMDD). No study has yet examined their association with mood in women with major depressive disorder (MDD). The purpose of this study was to determine whether estrogen-progestin combination or progestin-only contraceptives are associated with depression severity, function and quality of life, or general medical or psychiatric comorbidity in women with MDD. METHODS: This analysis focused on a large population of female outpatients less than 40 years of age with non-psychotic MDD who were treated in 18 primary and 23 psychiatric care settings across the US, using data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Baseline demographic and clinical information was gathered and compared between three groups based on hormonal use: combination (estrogen-progestin)(N=232), progestin-only (N=58), and no hormone treatment (N=948). RESULTS: Caucasians were significantly more likely to use combined hormone contraception. Women on progestin-only had significantly more general medical comorbidities; greater hypersomnia, weight gain and gastrointestinal symptoms; and worse physical functioning than women in either of the other groups. Those on combined hormone contraception were significantly less depressed than those with no hormone treatment by the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated. The combined hormone group also demonstrated better physical functioning and less obsessive-compulsive disorder (COCD) comorbidity than either of the other groups. CONCLUSIONS: Synthetic estrogen and progestins may influence depressive and physical symptoms in depressed women.

Russell JM, Weisberg R, Fava M, Hartford JT, Erickson JS, D'Souza DN. · Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. · Depress Anxiety. · Pubmed #17587217 No free full text.

Abstract: Anxiety disorders often are accompanied by painful physical symptoms. This report assessed the effectiveness of duloxetine in improving anxiety symptoms, pain severity, and patient functioning in adults diagnosed with generalized anxiety disorder (GAD), who presented with clinically significant pain symptoms. Data were pooled from two multicenter, randomized, double-blind, placebo-controlled clinical studies evaluating the efficacy of duloxetine 60-120 mg once daily compared with placebo in the treatment of GAD. The primary patient population for these analyses was patients with baseline Visual Analog Scale (VAS) overall pain severity score > or =30. Of the 798 randomized patients that had baseline VAS scores, approximately 44.4% of GAD patients were identified as having baseline VAS overall pain severity score > or =30 (duloxetine N=208, placebo N=146). Duloxetine-treated patients had significantly greater improvement compared with placebo-treated patients on anxiety symptoms (measured by Hamilton Anxiety Scale total score), on patient functioning (measured by the Sheehan Disability Scale Global Functional Impairment Score and across all Sheehan Disability Scale domains), and on all VAS pain items. Patients achieving remission at endpoint, and patients with lower scores on the Clinical Global Impression of Improvement and Patient Global Impression of Improvement scales had greater improvement in VAS pain severity scores. These results suggest that in patients with GAD who present with clinically significant pain symptoms, duloxetine is effective in reducing anxiety symptoms, pain severity, and in improving patient functioning.