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Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. doi: 10.1176/appi.ajp.2010.10040541

Objective: Family and twin studies indicate substantial overlap of genetic influences on psychotic and mood disorders. Linkage and candidate gene studies have also suggested overlap across schizophrenia, bipolar disorder, and major depressive disorder. The purpose of this study was to apply genomewide association study (GWAS) analysis to address the specificity of genetic effects on these disorders. Method: The authors combined GWAS data from three large effectiveness studies of schizophrenia (CATIE, genotyped: N=741), bipolar disorder (STEP-BD, genotyped: N=1,575), and major depressive disorder (STAR*D, genotyped: N=1,938) as well as from psychiatrically screened control subjects (NIMH-Genetics Repository: N=1,204). A two-stage analytic procedure involving an omnibus test of allele frequency differences among case and control groups was applied, followed by a model selection step to identify the best-fitting model of allelic effects across disorders. Results: The strongest result was seen for a single nucleotide polymorphism near the adrenomedullin (ADM) gene (rs6484218), with the best-fitting model indicating that the effect was specific to bipolar II disorder. Findings also revealed evidence suggesting that several genes may have effects that transcend clinical diagnostic boundaries, including variants in NPAS3 that showed pleiotropic effects across schizophrenia, bipolar disorder, and major depressive disorder. Conclusions: This study provides the first genomewide significant evidence implicating variants near the ADM gene on chromosome 11pl 5 in psychopathology, with effects that appear to be specific to bipolar II disorder. Although genomewide significant evidence of cross-disorder effects was not detected, the results provide evidence that there are both pleiotropic and disorder-specific effects on major mental illness and illustrate an approach to dissecting the genetic basis of mood and psychotic disorders that can inform future large-scale cross-disorder GWAS analyses.

Objective: Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington's disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established. Method: This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression. Results: CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats. Conclusions: In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles.

Objective: Phase III clinical trials for depression enroll participants with major depressive disorder according to stringent inclusion and exclusion criteria. These patients may not be representative of typical depressed patients seeking treatment. This analysis used data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) project--which used broad inclusion and minimal exclusion criteria--to evaluate whether phase III clinical trials recruit representative depressed outpatients. Method: Of 2,855 participants, 22.2% met typical entry criteria for phase III clinical trials (efficacy sample) and 77.8% did not (nonefficacy sample). These groups were compared regarding baseline sociodemographic and clinical features and the characteristics and outcomes of acute-phase treatment. Results: The efficacy sample had a shorter average duration of illness and lower rates of family history of substance abuse, prior suicide attempts, and anxious and atypical symptom features. Despite similar medication dosing and time at exit dose, the efficacy participants tolerated citalopram better. They also had higher rates of response (51.6% versus 39.1%) and remission (34.4% versus 24.7%). These differences persisted even after adjustments for baseline differences. Conclusions: Phase III trials do not recruit representative treatment-seeking depressed patients. Broader phase III inclusion criteria would increase the generalizability of results to practice, potentially reducing placebo response and remission rates (reducing the risk of failed trials) but at the risk of some increase in adverse events.

Objective: Maternal depression is a consistent and well-replicated risk factor for child psychopathology. The authors examined the changes in psychiatric symptoms and global functioning in children of depressed women 1 year following the initiation of treatment for maternal major depressive disorder. Method: Participants were 1) 151 women with maternal major depression who were enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 2) their eligible offspring who, along with the mother, participated in the child STAR*D (STAR*D-Child) study (mother-child pairs: N=151). The STAR*D study was a multisite study designed to determine the comparative effectiveness and acceptability of various treatment options for adult outpatients with nonpsychotic major depressive disorder. The STAR*D-Child study examined children of depressed women at baseline and involved periodic follow-ups for 1 year after the initiation of treatment for maternal major depressive disorder to ascertain the following data: 1) whether changes in children's psychiatric symptoms were associated with changes in the severity of maternal depression and 2) whether outcomes differed among the offspring of women who did and did not remit (mother-child pairs with follow-up data: N=123). Children's psychiatric symptoms in the STAR*D-Child study were assessed using the Schedule for Affective Disorders and Schizophrenia for School-Age Children--Present and Lifetime Version (K-SADS-PL), and maternal depression severity in the STAR*D study was assessed by an independent clinician, using the 17-item Hamilton Depression Rating Scale (HAM-D). Results: During the year following the initiation of treatment, maternal depression severity and children's psychiatric symptoms continued to decrease over time. Decreases in the number of children's psychiatric symptoms were significantly associated with decreases in maternal depression severity. When children's outcomes were examined separately, a statistically significant decrease in symptoms was evident in the offspring of women who remitted early (i.e., within the first 3 months after the initiation of treatment for maternal depression) or late (i.e., over the 1-year follow-up interval) but not in the offspring of nonremitting women. Conclusions: Continued efforts to treat maternal depression until remission is achieved are associated with decreased psychiatric symptoms and improved functioning in the offspring.

Objective: The authors compared fluoxetine and placebo in continuation treatment to prevent relapse of major depressive disorder in children and adolescents. Method: After a detailed evaluation, children and adolescents 7-18 years of age with major depressive disorder were treated openly with fluoxetine. Those who had an adequate response after 12 weeks, as indicated by a Clinical Global Impression improvement score of 1 or 2 and a decrease of at least 50% in Children's Depression Rating Scale--Revised score, were randomly assigned to receive fluoxetine or placebo for an additional 6 months. The primary outcome measures were relapse and time to relapse. Relapse was defined as either a score of 40 or higher on the Children's Depression Rating Scale with a history of 2 weeks of clinical deterioration, or clinical deterioration as judged by the clinician. Additional analyses were conducted with relapse de fined only as a score of 40 or higher on the Children's Depression Rating Scale. Results: Of 168 participants enrolled in acute fluoxetine treatment, 102 were randomly assigned to continuation treatment with fluoxetine (N=50) or placebo (N=52). Of these, 21 participants (42.0%) in the fluoxetine group relapsed, compared with 36 (69.2%) in the placebo group, a significant difference. Similarly, under the stricter definition of relapse, fewer participants in the fluoxetine group relapsed (N=11; 22.0%) than in the placebo group (N=25; 48.1%). Time to relapse was significantly shorter in the placebo group. Conclusions: Continuation treatment with fluoxetine was superior to placebo in preventing relapse and in increasing time to relapse in children and adolescents with major depression.

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.

Objective: Suicidal ideation is an uncommon symptom than can emerge during antidepressant treatment. The biological basis of treatment-emergent suicidal ideation is unknown. Genetic markers may shed light on the causes of treatment-emergent suicidal ideation and help identify individuals at high risk who may benefit from closer monitoring, alternative treatments, or specialty care. Method: A clinically representative cohort of outpatients with major depressive disorder who enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 1,915 participants were genotyped for 768 single-nucleotide polymorphisms in 68 candidate genes. Allele and genotype frequencies were compared between the 120 participants who developed treatment-emergent suicidal ideation and those who did not. Results: Two markers were significantly associated with treatment-emergent suicidal ideation in this sample (marker rs4825476, p=0.0000784, odds ratio= 1.94; permutation p=O.01; marker rs2518224, p=0.0000243, odds ratio= 8.23; permutation p=0.003). These markers reside within the genes GRIA3 and GRIK2, respectively, both of which encode ionotropic glutamate receptors. Conclusions: Markers within GRIK2 and GRIA3 were associated with treatment-emergent suicidal ideation during citalopram therapy. If replicated, these findings may shed light on the biological basis of this potentially dangerous adverse event and help identify patients at increased risk.

Objective: This report assesses whether age at onset defines a specific subgroup of major depressive disorder in 4,041 participants who entered the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Method: The study enrolled outpatients 18-75 years of age with nonpsychotic major depressive disorder from both primary care and psychiatric care practices. At study entry, participants estimated the age at which they experienced the onset of their first major depressive episode. This report divides the population into five age-at-onset groups: childhood onset (ages Results: No group clearly stood out as distinct from the others. Rather, the authors observed an apparent gradient, with earlier ages at onset associated with never being married, more impaired social and occupational function, poorer quality of life, greater medical and psychiatric comorbidity, a more negative view of life and the self, more lifetime depressive episodes and suicide attempts, and greater symptom severity and suicidal ideation in the index episode compared to those with later ages at onset of major depressive disorder. Conclusions: Although age at onset does not define distinct depressive subgroups, earlier onset is associated with multiple indicators of greater illness burden across a wide range of indicators. Age of onset was not associated with a difference in treatment response to the initial trial of citalopram.

Objective: An initial pharmacogenetic study of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial reported an association between genetic variation in the HTR2A gene and outcome of citalopram treatment. By design, the study analyzed only those markers that showed reproducible association in the first wave of genotypes (comprising 1,297 patients) in the complete cohort of patients. The purpose of the present study was to utilize a second wave of genotype results, for a more powerful analysis, in the complete cohort of patients with available deoxyribonucleic acid (DNA) samples. Method: The authors tested the association between treatment response and 768 markers that were genotyped in the full set of 1,816 eligible patients from the STAR*D cohort. In order to control for multiple testing, the subjects were divided into two study groups: discovery and replication. Results: In addition to the previously identified marker in the HTR2A gene, a new marker (rs1954787) in the GRIK4 gene, which codes for the kainic acid-type glutamate receptor KA1, was observed. The effect size of the GRIK4 marker alone was modest, but homozygote carriers of the treatment-response-associated marker alleles of both the GRIK4 and HTR2A genes were 23% less likely to experience nonresponse to treatment relative to participants who did not carry any of these marker alleles. Conclusions: The findings demonstrate that genetic variation in a kainic acid-type glutamate receptor is reproducibly associated with response to the antidepressant citalopram. This finding suggests that the glutamate system plays an important role in modulating response to selective serotonin reuptake inhibitors (SSRIs).

Objective: Premature attrition from treatment may lead to worse outcomes and compromise the integrity of clinical trials in major depressive disorder. The purpose of this study was to identify the pretreatment predictors of attrition during acute treatment with citalopram in a large, 'real world' clinical trial. Method: A total of 4,041 adult outpatients with nonpsychotic major depressive disorder were enrolled in treatment with citalopram for up to 14 weeks. Attrition was defined as 'immediate' (patients who attended a baseline visit only) or 'later' (patients who attended at least one postbaseiine visit but who dropped out before the 12-week visit). Results: Overall, 26% of enrolled patients dropped out of the acute phase treatment for nonmedical reasons. Of these, 34% dropped out immediately, 59% dropped out by week 12, and 7% dropped out after 12 weeks. Immediate attrition was associated with younger age, less education, and higher perceived mental health functioning. Attrition later in treatment was associated with younger age, less education, and African American race. Experience with more than one episode of depression was associated with less attrition. Conclusions: In clinical trials and clinical practice, several time points in treatment may provide opportunities to engage and encourage populations at higher risk for attrition and populations with high-risk presentation of illness. Additionally, more aggressive forms of treatment implemented earlier in the treatment process in order to increase the likelihood of more rapid efficacy may reduce dropout rates.

Objective: The authors compared the effectiveness of cognitive therapy and pharmacotherapy as second-step strategies for outpatients with major depressive disorder who had received inadequate benefit from an initial trial of citalopram. Cognitive therapy was compared with medication augmentation and switch strategies. Method: An equipoise-stratified randomization strategy was used to assign participants to either augmentation of citalopram with cognitive therapy (N=65) or medication (N=117; either sustained-release bupropion [N=56] or buspirone [N= 61]) or switch to cognitive therapy (N=36) or another antidepressant (N=86; sertraline [N=27], sustained-release bupropion [N=28], or extended-release venlafaxine [N=31]). Treatment outcomes and the frequency of adverse events were compared. Results: Less than one-third of participants consented to randomization strata that permitted comparison of cognitive therapy and pharmacotherapy. Among participants who were assigned to second-step treatment, those who received cognitive therapy (either alone or in combination with citalopram) had similar response and remission rates to those assigned to medication strategies. For those who continued on citalopram, medication augmentation resulted in significantly more rapid remission than augmentation with cognitive therapy. Among those who discontinued citalopram, there were no significant differences in outcome, although those who switched to a different antidepressant reported significantly more side effects than those who received cognitive therapy alone. Conclusions: After an unsatisfactory response to citalopram, patients who consented to random assignment to either cognitive therapy or alternative pharmacologic strategies had generally comparable outcomes. Pharmacologic augmentation was more rapidly effective than cognitive therapy augmentation of citalopram, whereas switching to cognitive therapy was better tolerated than switching to a different antidepressant.

Objective: Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches. Method: Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. Results: Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. Conclusions: Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment.

Objective: This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Method: A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N= 3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of [less than or equal to] 5 on the Quick Inventory of Depressive Symptomatology--Self-Report (QIDS-S[R.sub.16]) (equivalent to [less than or equal to] 7 on the 17-item Hamilton Rating Scale for Depression [HRS[D.sub.17]]) defined remission; a QIDS-S[R.sub.16] total score of [greater than or equal to] 11 (HRS[D.sub.17][greater than or equal to] 14) defined relapse. Results: The QIDS-S[R.sub.16] remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps. Conclusions: When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed. (Am J Psychiatry 2006; 163:1905-1917)

Objective: More than 40% of patients with major depressive disorder do not achieve remission even after two optimally delivered trials of antidepressant medications. This study compared the effectiveness of lithium versus triiodothyronine ([T.sub.3]) augmentation as a third-step treatment for patients with major depressive disorder. Method: A total of 142 adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or who were intolerant to an initial prospective treatment with citalopram and a second switch or augmentation trial were randomly assigned to augmentation with lithium (up to 900 rag/day; N=69) or with [T.sub.3] (up to 50 [micro]g/day: N-73) for up to 14 weeks. The primary outcome measure was whether participants achieved remission, which was defined as a score [less than or equal to] 7 on the 17-item Hamilton Depression Rating Scale. Results: After a mean of 9.6 weeks (SD= 5.2) of treatment, remission rates were 15.9% with lithium augmentation and 24.7% with [T.sub.3] augmentation, although the difference between treatments was not statistically significant. Lithium was more frequently associated with side effects (p=0.045), and more participants in the lithium group left treatment because of side effects (23.2% versus 9.6%; p= 0.027). Conclusions: Remission rates with lithium and [T.sub.3] augmentation for participants who experienced unsatisfactory results with two prior medication treatments were modest and did not differ significantly. The lower side effect burden and ease of use of [T.sub.3] augmentation suggest that it has slight advantages over lithium augmentation for depressed patients who have experienced several failed medication trials.

Objective: The purpose of this study was to compare the effectiveness and tolerability of tranylcypromine and combination treatment with extended-release venlafaxine and mirtazapine in patients with treatment-resistant major depression whose current depressive episode had not responded adequately to treatment in three prior prospective medication trials. Method: Adult outpatients with nonpsychotic major depressive disorder who had not achieved remission or had withdrawn from treatment because of intolerance in three previous prospective medication trials were randomly assigned to receive open-label treatment with either tranylcypromine (N=58) or extended-release venlafaxine plus mirtazapine (N=51). The primary outcome measure was whether patients achieved remission, which was defined as a score [less than or equal to] 7 at exit on the 17-item Hamilton Depression Rating Scale (HAM-D). The HAM-D was administered by telephone by raters to whom treatment was masked. Results: Remission rates were not significantly different between the two treatment groups (6.9% for the tranylcypromine group and 13.7% for the venlafaxine plus mirtazapine group). The mean daily dose at exit for tranylcypromine was 36.9 mg (SD=18.5); for venlafaxine, 210.3 mg (SD=95.2); and for mirtazapine, 35.7 mg (SD=17.6). Tranylcypromine was associated with significantly less symptom reduction and greater attrition due to intolerance. Conclusions: Remission rates were modest for both the tranylcypromine group and the extended-release venlafaxine plus mirtazapine group, and the rates were not statistically different between groups. The lower side effect burden, lack of dietary restrictions, and ease of use of venlafaxine and mirtazapine suggest that this combination may be preferred over tranylcypromine for patients with highly treatment-resistant depression who have not benefited adequately from several prior treatments.

Objective: Few controlled studies have addressed the issue of which antidepressant medications should be recommended for outpatients who have not responded to multiple treatment trials. This study compared the efficacy of switching to mirtazapine to that of switching to a tricyclic antidepressant (nortriptyline) following two prospective, consecutive, unsuccessful medication treatments for nonpsychotic major depressive disorder. Method: Following lack of remission or an inability to tolerate an initial trial of citalopram for up to 12 weeks (first step) and a second trial with either monotherapy involving another antidepressant or augmentation of citalopram with bupropion or buspirone (second step), adult outpatients (N=235) with nonpsychotic major depressive disorder were randomly assigned to 14 weeks of treatment with mirtazapine (up to 60 mg/day) (N=114) or nortriptyline (up to 200 m/day) (N=121). The primary outcome, symptom remission, was defined a priori as a total exit score of [less than or equal to] 7 on the 17-item Hamilton Rating Scale for Depression. The 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-[SR.sub.16]), obtained at treatment visits, provided secondary outcomes of remission (score [less than or equal to] 5 at exit) and response ([greater that or equal to] 50% reduction in score from baseline). Results: For mirtazapine, remission rates were 12.3% and 8.0% per the Hamilton and QIDS-[SR.sub.16] scores, respectively. For nortriptyline, remission rates were 19.8% and 12.4%, respectively. QIDS-[SR.sub.16] response rates were 13.4% for mirtazapine and 16.5% for nortriptyline. Neither response nor remission rates statistically differed by treatment, nor did these two treatments differ in tolerability or adverse events. Conclusions: Switching to a third antidepressant monotherapy regimen after two consecutive unsuccessful antidepressant trials resulted in low remission rates (

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 [less than or equal to] 7 on the 17-item Hamilton Depression Rating Scale (HAM-D) (primary outcome) or a score of [less than or equal to] 5 on the 16-item Quick Inventory of Depressive Symptomatology, Self-Report (QIDS-SR) (secondary outcome). Response was defined as a reduction of [greater than or equal to] 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.

Objective: This study assessed the incidence, severity, and course of expressed suicidal intent in depressed patients who were treated with ECT. The data are from the first phase of an ongoing, collaborative multicenter study, the overall aim of which was to compare continuation ECT with pharmacotherapy in the prevention of relapse after a successful course of ECT. Method: Suicidal intent, as expressed by patients during an interview, was scored at baseline and before each ECT session with item 3 on the 24-item Hamilton Depression Rating Scale in 444 patients with unipolar depression. Results: One hundred thirty-one patients (29.5%) reported suicidal thoughts and acts (score of 3 or 4) at baseline. Scores decreased to 0 after 1 week (three ECT sessions) in 38.2% of the patients, after 2 weeks (six ECT sessions) in 61.1%, and in 80.9% at the end of the course of treatment. Conclusions: Expressed suicidal intent in depressed patients was rapidly relieved with ECT. Evidence-based treatment algorithms for major depressive mood disorders should include dichotomization according to suicide risk, as assessed by interview. For patients at risk, ECT should be considered earlier than at its conventional 'last resort' position.

Objective: The purpose of this study was to determine whether adjunctive use of a psychostimulant (mixed amphetamine salts) was safe and efficacious for treatment of symptoms of attention deficit hyperactivity disorder (ADHD) in pediatric outpatients with bipolar I or bipolar II disorder and concurrent ADHD whose manic symptoms had been stabilized through treatment with divalproex sodium. Method: An 8-week open-label trial of divalproex sodium to control manic symptoms and to discern the effect of divalproex sodium on ADHD was followed by a 4-week randomized, double-blind, placebo-controlled crossover trial to determine if mixed amphetamine salts was safe and effective for treatment of ADHD symptoms. Patients in the crossover trial continued to receive divalproex sodium. Diagnoses, made by clinical interview, were confirmed with the Washington University in St. Louis Kiddie Schedule for Affective Disorders and Schizophrenia. The Young Mania Rating ScaLe (for manic symptoms) and the Clinical Global Impression of improvement (for ADHD symptoms) were the primary outcome measures. Results: Forty subjects ages 6-17 years with bipolar I disorder (77.5%) or bipolar II disorder (22.5%) and a Young Mania Rating Scale score [greater than or equal] 14 entered open treatment with divalproex sodium. With divalproex sodium, 32 subjects achieved [greater than or equal] 50% reduction in Young Mania Rating Scale baseline scores, but only three participants had significant improvement in ADHD symptoms. For the 30 subjects who entered the placebo-controlled crossover trial, mixed amphetamine salts was significantly more effective than placebo for ADHD symptoms. No significant side effects or worsening of manic symptoms was observed. Conclusions: Pediatric patients with bipolar disorder and concurrent ADHD can be safely and effectively treated with mixed amphetamine salts after their manic symptoms are stabilized with divalproex sodium. Divalproex sodium alone (8-week trial) is not an effective treatment for ADHD in the context of bipolar disorder.

Objective: Minor depressive disorder is both common and associated with significant psychosocial impairment. This study examined antidepressant treatment efficacy in a large group of patients with minor depressive disorder. Method: One hundred sixty-two patients with minor depressive disorder were randomly assigned to receive fluoxetine or placebo in a 12-week, double-blind study; 73% (59 of 81) of the patients in each treatment group completed the study. Patients were evaluated weekly with standard depression rating instruments and measures of psychosocial impairment. Hypotheses were tested by last-observation-carried-forward analysis of variance (ANOVA) and confirmed by mixed (random-effects) regression analysis. Results: At baseline, minor depressive disorder patients were mildly to moderately depressed, with a corresponding degree of functional impairment. Over 12 weeks of treatment, both ANOVA and mixed regression showed fluoxetine to be superior to placebo as indicated by significantly greater improvement of fluoxetine-treated patients in scores on the 30 item clinician rated Inventory of Depressive Symptomatology, the 17-item and 21 item Hamilton Depression Rating Scale, the Beck Depression Inventor% and the Clinical Global Impression severity scale. Improvement in Global Assessment of Functioning Scale score was significantly greater for the fluoxetine group in mixed regression analysis only. Patients in both treatment groups reported a similar number and severity of adverse events during the 12-week treatment period. Conclusions: Clinicians frequently encounter minor depressive disorder either as a prodromal or residual phase of illness in major depressive disorder or as de novo minor depressive disorder episodes. Fluoxetine is significantly superior to placebo in reducing minor depressive disorder symptoms within a 12-week period. Improvement in psychosocial function with fluoxetine may take longer than 12 weeks.

Objective: The authors provide a detailed clinical description of minor depression: its symptoms, level of disability, stability, and relationship to patient and family history of major depressive disorder. Method: Rigorous criteria for minor depression, including functional disability, were used to identify 226 individuals for a three-phase treatment study. This report presents data obtained on that study group during the first study phase, a 4-week placebo lead-in period. Results: One hundred sixty-two subjects (72% of the initial study group) remained in the study for 4 weeks and continued to meet criteria for minor depression. Minor depression in these subjects was primarily characterized by mood and cognitive symptoms, not the classical neurovegetative signs and symptoms of depression. Approximately one-third of the subjects with minor depression had a past history of major depressive disorder, and nearly half had a family history of unipolar depressive disorder; however, neither factor affected the severity or quality of minor depressive symptoms. Conclusions: These data suggest that 1) minor depression is not evanescent; 2) minor depression is characterized by mood and cognitive symptoms rather than neurovegetative symptoms; 3) minor depression may occur either independently of a lifetime history of major depressive disorder or as a stage of illness in the course of recurrent unipolar depressive disorder; and 4) depressive disorders should be conceptualized as a continuum of severity.

Objective: Postpartum depressive disorders lead to maternal disability and disturbed mother-infant relationships, but information regarding the rates of major depressive disorder in minority women is noticeably lacking. The goal of this study was to determine whether the risk factors for and rate of postpartum major depressive disorder in a predominantly African American and Hispanic clinic population would be similar to those reported for Caucasian women. Method: Investigators systematically screened all women scheduled for their first postpartum visit on selected days at four publicly funded inner-city community maternal health clinics in Dallas County (N=802). A multistage screening process included the Edinburgh Postnatal Depression Scale, the Inventory of Depressive Symptomatology, and the Structured Clinical Interview for DSM-IV for a maximum of three assessments during the initial 3-5-week postpartum period. Results: The estimated rate of major depressive disorder during the postpartum period among women in this setting was between 6.5% and 8.5%. Only 50% of the depressed women reported onset following birth. Bottle-feeding and not living with one's spouse or significant other were associated with depression at the first evaluation; persistent depressive symptoms were linked with the presence of other young children at home. Greater severity of depressive symptoms at first contact predicted major depressive disorder several weeks later. Conclusions: Rates of postpartum depression among Latina and African American postpartum women are similar to epidemiologic rates for Caucasian postpartum and nonpostpartum women. As previously shown for Caucasian women, major depressive disorder in many Latina and African American postpartum women begins before delivery, revealing the need to screen pregnant women for depression. (Am J Psychiatry 2001; 158:1856-1863)

Objective: Case series and follow-up studies suggest that clozapine may have mood-stabilizing properties in addition to antipsychotic action in patients with schizoaffective disorder, bipolar type, and bipolar I disorder, but the generalizability of these findings is limited. This article describes a randomized, open study of clozapine add-on therapy versus treatment as usual for patients with treatment-resistant illness and a history of mania. Method: Thirty-eight patients meeting the DSM-IV criteria for schizoaffective or bipolar disorder that was deemed treatment-resistant were randomly assigned to clozapine add-on treatment (N = 19) or treatment as usual (no clozapine) (N = 19) and followed up for 1 year. Patients received monthly ratings on the Brief Psychiatric Rating Scale, Clinical Global Impression scale, Bech-Rafaelsen Mania Scale, Hamilton Depression Rating Scale, Scale for the Assessment of Positive Symptoms, Scale for the Assessment of Negative Symptoms, Abnormal Involuntary Movement Scale, and a 40-item side effect checklist. Differences between treatment groups were assessed according to a pattern-mix random-regression model. An additional analysis compared group differences in rating scale scores against relative time in the study. Results: Significant between-group differences were found in scores on all rating scales except the Hamilton depression scale. Total medication use over 1 year significantly decreased in the clozapine group. No significant differences between groups in somatic complaints were noted. The subjects with nonpsychotic bipolar I disorder who received clozapine showed a degree of improvement similar to that of the entire clozapine-treated group. Clozapine dose was significantly higher for the patients with schizoaffective illness than for those with bipolar disorder. Conclusions: The results of this study support clozapine's independent mood-stabilizing property. They demonstrate that clozapine use was associated with significant clinical improvement relative to treatment as usual.

Objective: The purpose of this article is to provide an overview of existing systems for the diagnosis of the endogenous (melancholic) subtype of major depression. Method: The authors review the critical empirical research examining this subtype and discuss its implications for DSM-IV. They examine the relationship of endogenous/melancholic symptoms to other clinical features, treatment response, selected laboratory tests, consistency across episodes, family history, and particular courses of illness. Results: Melancholic symptom features are predictive of a positive response to ECT and to tricyclic antidepressants in the severely ill. Key features include psychomotor retardation, unreactive mood, pervasive anhedonia, and distinct quality of mood. Melancholic features are associated with shorter REM latency and/or nonsuppression of cortisol during the dexamethasone suppression test. Depressive episodes that are not melancholic may take on melancholic features with repetition and passage of time in some individuals. Once melancholic features are present, it is unclear whether they repeat across subsequent episodes. Melancholic features are not uniquely associated with a positive family history of depression per se, but they may be especially associated with a family history of severe depression. Conclusions: The available evidence suggests some clinical utility and some (albeit not entirely consistent) validity for the concept of melancholic features. Consequently, DSM-IV will retain the designation 'with melancholic features,' return to the shorter DSM-III feature listing, and broaden the designation by requiring either unreactive mood or pervasive anhedonia but not both. Further research on this subgroup is indicated.