Depression epidemiology and its treatment evolution.

Approximately 1 in 5 US adults have at least one episode of major depression in their lifetime. Of those who do, the majority will relapse over the long term and many will have psychosocial disabilities and reduced functioning. Over the past century, a range of medications have been developed to treat depression, although some effective medications have been superseded by newer treatments with an improved safety and tolerability profile. A reconsideration of some older medications is warranted until agents with truly novel mechanisms of action and good safety and tolerability profiles are available.

The epidemiology of depression and the evolution of treatment.

Depression is a prevalent and pernicious disorder. About 1 in 5 US adults have at least 1 lifetime episode of major depression. Of those with depression, the majority will relapse over the long-term and many will have poor mental health outcomes and psychosocial disabilities. Over the past century, a range of treatments, including medications with varying mechanisms of action, have been developed to manage depression. Treatments from seizure therapies to an array of medications--amphetamine, tricyclic antidepressants, monoamine oxidase inhibitors, mixed-action antidepressants, selective serotonin reuptake inhibitors, and dual reuptake inhibitors--have evolved.

A randomized, placebo-controlled, multicenter study of divalproex sodium extended-release in the acute treatment of mania.

OBJECTIVE: Divalproex sodium extended-release (ER) was examined for the treatment of acute mania in adults in 2 randomized, placebo-controlled clinical trials. One study demonstrated statistically significant improvements in mania symptoms compared to placebo, while an earlier study did not. Results of the earlier study are presented here. METHOD: A total of 225 DSM-IV-diagnosed bipolar I disorder patients were randomly assigned in a 2:1 ratio to 21 days of double-blind treatment with divalproex ER (n = 147) or placebo (n = 78). The daily divalproex ER dosage was initiated at 20 mg/kg. The primary efficacy variable was the change from baseline to final evaluation in Mania Rating Scale (MRS) score. Subjects were discontinued from the study if they were discharged from the hospital or if they met prespecified improvement criteria. The study was conducted from May 1998 to July 1999 at centers in the United States. RESULTS: There was no statistically significant difference in MRS score change from baseline to final for patients treated with divalproex ER compared with those treated with placebo. With the exception of back pain and constipation, adverse event rates between placebo and divalproex ER were very similar. A large proportion of patients prematurely discontinued study treatment (divalproex ER: 83%, placebo: 82%). The mean daily dose of divalproex ER was 2,211 mg with a mean maximum serum valproic acid concentration of 77.9 microg/mL. CONCLUSIONS: The results of the current study did not demonstrate statistically significant improvement in mania symptoms associated with divalproex ER treatment compared to placebo. A number of methodological considerations may have contributed to the negative findings, including allowance for early study discontinuation and lower than optimal dosing. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00060905.

Diagnostic guidelines for bipolar depression: a probabilistic approach.

OBJECTIVES: There are currently no accepted diagnostic criteria for bipolar depression for either research or clinical purposes. This paper aimed to develop recommendations for diagnostic criteria for bipolar I depression. METHODS: Studies on the clinical characteristics of bipolar and unipolar depression were reviewed. To identify relevant papers, literature searches using PubMed and Medline were undertaken. RESULTS: There are no pathognomonic characteristics of bipolar I depression compared to unipolar depressive disorder. There are, however, replicated findings of clinical characteristics that are more common in both bipolar I depression and unipolar depressive disorder, respectively, or which are observed in unipolar-depressed patients who 'convert' (i.e., who later develop hypo/manic symptoms) to bipolar disorder over time. The following features are more common in bipolar I depression (or in unipolar 'converters' to bipolar disorder): 'atypical' depressive features such as hypersomnia, hyperphagia, and leaden paralysis; psychomotor retardation; psychotic features, and/or pathological guilt; and lability of mood. Furthermore, bipolar-depressed patients are more likely to have an earlier age of onset of their first depressive episode, to have more prior episodes of depression, to have shorter depressive episodes, and to have a family history of bipolar disorder. The following features are more common in unipolar depressive disorder: initial insomnia/reduced sleep; appetite, and/or weight loss; normal or increased activity levels; somatic complaints; later age of onset of first depressive episode; prolonged episodes; and no family history of bipolar disorder. CONCLUSIONS: Rather than proposing a categorical diagnostic distinction between bipolar depression and major depressive disorder, we would recommend a 'probabilistic' (or likelihood) approach. While there is no 'point of rarity' between the two presentations, there is, rather, a differential likelihood of experiencing the above symptoms and signs of depression. A table outlining draft proposed operationalized criteria for such an approach is provided. The specific details of such a probabilistic approach need to be further explored. For example, to be useful, any diagnostic innovation should inform treatment choices.

Screening for bipolar disorder in a county jail at the time of criminal arrest.

OBJECTIVE: This study assessed the operating characteristics of the mood disorder questionnaire (MDQ) among offenders arrested and detained at a county jail. METHOD: The MDQ, a brief self-report instrument designed to screen for all subtypes of bipolar disorder (BP I, II and NOS) was voluntarily administered to adult detainees at the Ottawa County Jail in Port Clinton, Ohio. A confirmatory diagnostic evaluation was also performed using the mini-international neuropsychiatric interview (MINI). The MDQ was scored using a standard algorithm requiring endorsement of 7/13 mood items as well as two items that assess whether manic or hypomanic symptoms co-occur and cause moderate to severe functional impairment. In addition to the standard algorithm for scoring the MDQ, modifications were also tested in an attempt to improve overall sensitivity. RESULTS: Among 526 jail detainees who completed the MDQ, 37 (7%) screened positive for bipolar disorder. Of 164 detainees who agreed to a research diagnostic evaluation, 32 (19.5%) screened positive on the MDQ, while 55 (33.5%) met criteria for bipolar disorder according to the MINI. When administered to the sample of 164 adult jail detainees, the sensitivity of the MDQ was 0.47 and the specificity was 0.94. The MDQ was significantly better at detecting BP I (0.59) than BP II/NOS (0.19; p=0.008). Modification of scoring the MDQ improved the sensitivity for detection of BP II from 0.23 to 0.54 with minimal decrease in specificity (0.84). The optimum sensitivity and specificity of the MDQ was achieved by decreasing the item threshold to 3/13 and eliminating the symptom co-occurrence and functional impairment items. CONCLUSION: The MDQ was found to have limited utility as a screening tool for bipolar disorder in a correctional setting, particularly for the BP II subtype.

Screening for bipolar disorder.

Bipolar disorder is a recurrent and sometimes chronic illness involving episodes of depression and mania or hypomania. The most frequent presentation is depression: more than 1 of 5 primary care patients with depression have bipolar disorder. The symptoms of bipolar depression often differ from those of unipolar depression. Age of onset for bipolar disorder is usually the late teens; slightly older for bipolar II subtype. Nearly all patients with bipolar disorder suffer from a comorbid psychiatric disorder, most frequently an anxiety disorder. Although the most dramatic presentation of bipolar disorder is the acutely manic patient who presents to the emergency department, this presentation is much less frequently encountered in physicians' offices, both primary care and psychiatric. Bipolarity is often missed in these situations. About half of bipolar patients have consulted 3 or more professionals before receiving a correct diagnosis, and the average time to first treatment is 10 years. It is imperative that clinicians carefully assess patients for bipolar disorder, especially those presenting with depression. In addition to patient and family history, administration of a screening instrument can be very helpful. The most widely used screening tool is the Mood Disorder Questionnaire. This screening tool will be discussed in this article regarding its use in outpatient clinics and the community.

The Prevention of Recurrent Episodes of Depression with Venlafaxine for Two Years (PREVENT) Study: Outcomes from the 2-year and combined maintenance phases.

OBJECTIVE: To report second-year results from the 2-year maintenance phase of a long-term study to evaluate the efficacy and safety of venlafaxine extended release (ER) in preventing recurrence of depression. METHOD: Outpatients with recurrent unipolar depression (DSM-IV criteria; N = 1096) were randomly assigned in a 3:1 ratio to 10 weeks of treatment with venlafaxine ER or fluoxetine. Responders (17-item Hamilton Rating Scale for Depression [HAM-D(17)] total score or= 50% decrease from baseline) entered a 6-month, double-blind continuation phase on the same medication. Continuation-phase responders were enrolled into maintenance treatment consisting of 2 consecutive 12-month phases. At the start of each maintenance phase, venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo, and fluoxetine responders were continued for each period. The second 12-month maintenance phase compared the time to recurrence of depression with venlafaxine ER (75 to 300 mg/day) versus placebo as the primary efficacy measure. The primary definition of recurrence was a HAM-D(17) total score > 12 and < 50% reduction from baseline (acute phase) at 2 consecutive visits or at the last valid visit prior to discontinuation. The time to recurrence was evaluated using Kaplan-Meier methods and compared between the venlafaxine ER and placebo groups using log-rank tests. Secondary outcome measures included rates of response and remission (defined as HAM-D(17)

Prevention of recurrent episodes of depression with venlafaxine ER in a 1-year maintenance phase from the PREVENT Study.

OBJECTIVES: To test the long-term efficacy and safety of venlafaxine extended-release (ER) in preventing recurrence in patients with major depression. METHOD: This multiple-phase study, entitled "Prevention of Recurrent Episodes of Depression With Venlafaxine for Two Years" (PREVENT), was conducted from December 2000 through July 2005 in patients with recurrent unipolar depression (DSM-IV) who were initially randomly assigned to double-blind treatment with venlafaxine ER (75 mg/day to 300 mg/day) or fluoxetine (20 mg/day to 60 mg/day) for 10 weeks of acute treatment. Responders then received 6 months of continuation treatment. Those who remained responders were then enrolled into a 12-month maintenance period. Venlafaxine ER responders were randomly assigned to receive double-blind treatment with venlafaxine ER or placebo. Fluoxetine responders were not randomly assigned but continued taking fluoxetine in order to maintain the blind during the maintenance study. Time to recurrence of depression (17-item Hamilton Rating Scale for Depression total score > 12 and < 50% reduction from acute phase baseline) with venlafaxine ER versus that of placebo were compared. RESULTS: The efficacy evaluable sample consisted of 129 patients in each group. The mean daily dose of venlafaxine ER was 224.7 mg (SD = 66.7). The cumulative probability of recurrence through 12 months, based on the primary definition, was 23.1% (95% CI = 15.3 to 30.9) for venlafaxine ER and 42.0% (95% CI = 31.8 to 52.2) for placebo (p = .005, log-rank test). CONCLUSION: Patients who had been successfully treated with venlafaxine ER during acute and continuation therapy were significantly less likely to experience recurrence with venlafaxine ER than with placebo over a 12-month maintenance treatment period. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00046020.

Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication.

CONTEXT: There is growing recognition that bipolar disorder (BPD) has a spectrum of expression that is substantially more common than the 1% BP-I prevalence traditionally found in population surveys. OBJECTIVE: To estimate the prevalence, correlates, and treatment patterns of bipolar spectrum disorder in the US population. DESIGN: Direct interviews. SETTING: Households in the continental United States. PARTICIPANTS: A nationally representative sample of 9282 English-speaking adults (aged >or=18 years). MAIN OUTCOME MEASURES: Version 3.0 of the World Health Organization's Composite International Diagnostic Interview, a fully structured lay-administered diagnostic interview, was used to assess DSM-IV lifetime and 12-month Axis I disorders. Subthreshold BPD was defined as recurrent hypomania without a major depressive episode or with fewer symptoms than required for threshold hypomania. Indicators of clinical severity included age at onset, chronicity, symptom severity, role impairment, comorbidity, and treatment. RESULTS: Lifetime (and 12-month) prevalence estimates are 1.0% (0.6%) for BP-I, 1.1% (0.8%) for BP-II, and 2.4% (1.4%) for subthreshold BPD. Most respondents with threshold and subthreshold BPD had lifetime comorbidity with other Axis I disorders, particularly anxiety disorders. Clinical severity and role impairment are greater for threshold than for subthreshold BPD and for BP-II than for BP-I episodes of major depression, but subthreshold cases still have moderate to severe clinical severity and role impairment. Although most people with BPD receive lifetime professional treatment for emotional problems, use of antimanic medication is uncommon, especially in general medical settings. CONCLUSIONS: This study presents the first prevalence estimates of the BPD spectrum in a probability sample of the United States. Subthreshold BPD is common, clinically significant, and underdetected in treatment settings. Inappropriate treatment of BPD is a serious problem in the US population. Explicit criteria are needed to define subthreshold BPD for future clinical and research purposes.

Validity of the assessment of bipolar spectrum disorders in the WHO CIDI 3.0.

OBJECTIVE: Although growing interest exists in the bipolar spectrum, fully structured diagnostic interviews might not accurately assess bipolar spectrum disorders. A validity study was carried out for diagnoses of threshold and sub-threshold bipolar disorders (BPD) based on the WHO Composite International Diagnostic Interview (CIDI) in the National Comorbidity Survey Replication (NCS-R). CIDI BPD screening scales were also evaluated. METHOD: The NCS-R is a nationally representative US household population survey (n=9282 using CIDI to assess DSM-IV disorders. CIDI diagnoses were evaluated in blinded clinical reappraisal interviews using the non-patient version of the Structured Clinical Interview for DSM-IV (SCID). RESULTS: Excellent CIDI-SCID concordance was found for lifetime BP-I (AUC=.99 kappa=.88, PPV=.79, NPV=1.0), either BP-II or sub-threshold BPD (AUC=.96, kappa=.88, PPV=.85, NPV=.99), and overall bipolar spectrum disorders (i.e., BP-I/II or sub-threshold BPD; AUC=.99, kappa=.94, PPV=.88, NPV=1.0). Concordance was lower for BP-II (AUC=.83, kappa=.50, PPV=.41, NPV=.99) and sub-threshold BPD (AUC=.73, kappa=.51, PPV=.58, NPV=.99). The CIDI was unbiased compared to the SCID, yielding a lifetime bipolar spectrum disorders prevalence estimate of 4.4%. Brief CIDI-based screening scales detected 67-96% of true cases with positive predictive value of 31-52%. LIMITATION: CIDI prevalence estimates are still probably conservative, though, but might be improved with future CIDI revisions based on new methodological studies with a clinical assessment more sensitive than the SCID to sub-threshold BPD. CONCLUSIONS: Bipolar spectrum disorders are much more prevalent than previously realized. The CIDI is capable of generating conservative diagnoses of both threshold and sub-threshold BPD. Short CIDI-based scales are useful screens for BPD.

Prevalence and effects of mood disorders on work performance in a nationally representative sample of U.S. workers.

OBJECTIVE: Research on the workplace costs of mood disorders has focused largely on major depressive episodes. Bipolar disorder has been overlooked both because of the failure to distinguish between major depressive disorder and bipolar disorder and by the failure to evaluate the workplace costs of mania/hypomania. METHOD: The National Comorbidity Survey Replication assessed major depressive disorder and bipolar disorder with the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) and work impairment with the WHO Health and Work Performance Questionnaire. A regression analysis of major depressive disorder and bipolar disorder predicting Health and Work Performance Questionnaire scores among 3,378 workers was used to estimate the workplace costs of mood disorders. RESULTS: A total of 1.1% of the workers met CIDI criteria for 12-month bipolar disorder (I or II), and 6.4% meet criteria for 12-month major depressive disorder. Bipolar disorder was associated with 65.5 and major depressive disorder with 27.2 lost workdays per ill worker per year. Subgroup analysis showed that the higher work loss associated with bipolar disorder than with major depressive disorder was due to more severe and persistent depressive episodes in those with bipolar disorder than in those with major depressive disorder rather than to stronger effects of mania/hypomania than depression. CONCLUSIONS: Employer interest in workplace costs of mood disorders should be broadened beyond major depressive disorder to include bipolar disorder. Effectiveness trials are needed to study the return on employer investment of coordinated programs for workplace screening and treatment of bipolar disorder and major depressive disorder.

Validation of the Mood Disorder Questionnaire for bipolar disorders in adolescents.

OBJECTIVE: The study was designed to determine the validity of the Mood Disorder Questionnaire-Adolescent Version (MDQ-A) as a screening instrument for bipolar disorders (I, II, not otherwise specified, and cyclothymia) in an adolescent outpatient psychiatric population. METHOD: 104 adolescents and their parents completed the MDQ-A. Three versions of the MDQ-A were compared: (1) self report of symptoms by adolescent, (2) attributional report-how the adolescent believed teachers or friends would report his/her symptoms, and (3) parent report of adolescent's symptoms. DSM-IV diagnosis was made based upon the clinician-administered Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), a semistructured diagnostic interview. MDQ-A items were summed, yielding a score for each adolescent ranging from 0 to 13 on each of the 3 MDQ-A versions. Each possible scoring threshold, in combination with co-occurrence of symptoms and behaviors and with moderate to serious problems caused by symptoms, was crossed with the results of the K-SADS-PL diagnostic interview to assess sensitivity and specificity. The study was conducted from April 2002 to September 2003. RESULTS: A score of 5 or more items on the parent version yielded a sensitivity of 0.72 and specificity of 0.81, which were superior to self and attributional versions. CONCLUSIONS: The MDQ-A completed by parents about their adolescents' symptoms may be a useful screening instrument for bipolar disorders in an adolescent psychiatric outpatient population.