Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

OBJECTIVE: As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP-1) and bipolar II (BP-II) sub-types, we sought to generate empirically based criteria. METHOD: We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF-diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs. RESULTS: The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM-5 requires impaired functioning, we established that a high percentage of individuals with a BP-I or a BP-II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub-types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM-5 bipolar symptom criteria. CONCLUSION: This second-stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP-I and BP-II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP-I versus a BP-II condition.

Dawn simulation and bright light in the treatment of SAD: a controlled study.

BACKGROUND: Some small controlled studies have found that dawn simulation is effective in treating seasonal affective disorder (SAD). With a larger sample size and a longer duration of treatment, we compared dawn simulation with bright light therapy and a placebo condition in patients with SAD. METHOD: Medication-free patients with SAD were randomly assigned to one of three conditions: bright light therapy (10,000 lux for 30 min, from 6:00 AM to 6:30 AM), dawn simulation (1.5 hour dawn signal from 4:30 AM to 6:00 AM peaking at 250 lux), and a placebo condition, a dim red light (1.5 hour dawn signal from 4:30 am to 6:00 AM peaking at 0.5 lux.) Over the subsequent 6 weeks, the subjects were blindly rated by a psychiatrist using the Structured Interview Guide for the Hamilton Depression Rating-Seasonal Affective Disorder Version (SIGH-SAD). We modeled the profiles of the remissions (SIGH-SAD < or = 8) and response (> or =50% decrease in SIGH-SAD) to treatment over time using Cox proportional hazards models. RESULTS: The sample consisted of 95 subjects who were randomized to the three conditions: bright light (n = 33), dawn simulation (n = 31) and placebo (n = 31). Dawn simulation was associated with greater remission (p <.05) and response (p <.001) rates compared to the placebo. Bright light did not differ significantly from the placebo. Dawn simulation was associated with greater remission (p <.01) and response (p <.001) rates compared to the bright light therapy. The mean daily hours of sunshine during the week before each visit were associated with a significant increase in likelihood of both remission (p <.001) and response (p <.001). CONCLUSIONS: Dawn simulation was associated with greater remission and response rates compared to the placebo and compared to bright light therapy. The hours of sunshine during the week before each assessment were associated with a positive clinical response.

Efficacy and safety of mirtazapine in major depressive disorder patients after SSRI treatment failure: an open-label trial.

OBJECTIVE: To evaluate the efficacy and safety of mirtazapine in depressed outpatients who have shown nonresponse or intolerance to selective serotonin reuptake inhibitor (SSRI) therapy. METHOD: In this open-label, 8-week study, the efficacy and safety of mirtazapine among 103 outpatients with DSM-IV major depressive disorder who had failed previous therapy with an SSRI (fluoxetine, paroxetine, or sertraline) were evaluated. The primary efficacy measure was the 17-item Hamilton Rating Scale for Depression (HAM-D-17), and safety assessments included reported adverse events, routine laboratory assessments, physical examinations, and assessments of vital signs. A 4-day washout period followed by mirtazapine treatment was compared with an immediate switch from the SSRI to mirtazapine. RESULTS: Based on mean HAM-D-17 scores at endpoint and response rates of 48% based on the criterion of > or = 50% reduction in HAM-D-17 score, mirtazapine was found to be an effective treatment for a substantial proportion of patients for whom an SSRI was ineffective and/or poorly tolerated. Mirtazapine was well tolerated, with sedation and appetite increase/weight gain the most commonly reported adverse events. In addition, no difference in efficacy, safety, or tolerability was observed for patients undergoing an immediate switch from an SSRI (after having been tapered to the minimal effective dose) to mirtazapine, compared with those undergoing the imposition of a 4-day drug-free washout. CONCLUSION: These results suggest that an immediate switch to mirtazapine may be a valid therapeutic option among patients who cannot tolerate or do not respond to SSRIs.

Effectiveness of St John's wort in major depression: a randomized controlled trial.

CONTEXT: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation. OBJECTIVE: To compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States. PARTICIPANTS: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20. INTERVENTION: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I). RESULTS: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively). CONCLUSION: In this study, St John's wort was not effective for treatment of major depression.

Acute and maintenance treatment of chronic depression.

Chronic forms of depression account for approximately one third of all depressions. They are underrecognized and undertreated. This article defines the types of chronic depressions (dysthymic disorder, double depression, chronic major depression, and major depression in incomplete remission). A review of treatments for patients with these conditions is provided. The basic principles of treatment of chronic depression involve longer treatment and higher doses than are usually required for acute major depression. The impact of psychosocial disability and severity of depressive symptoms can be ameliorated with appropriate treatment. Newer treatments, such as the combination of psychotherapy and pharmacotherapy, may prove to be of greatest benefit for individuals with chronic mood disorders.

Management of anxiety disorders: the added challenge of comorbidity.

Patients with anxiety present with a wide variety of disorders that cause significant impairment to their everyday lives. To complicate matters, patients seldom present with just one anxiety disorder. Such comorbidity, particularly where depression is also present, has important implications for both the patient and the physician. The patient typically suffers from a greater degree of everyday impairment, is more reliant on healthcare services, in particular mental health services, and may be at a greater risk of attempting suicide. For the physician, comorbidity in anxiety disorders presents a challenge as the patient's symptoms are often more severe, present earlier in life, and are frequently prolonged which makes their management more complex. This review will focus on the anxiety disorders: panic disorder, obsessive-compulsive disorder, social anxiety disorder, and post-traumatic stress disorder. The impact of co-existing multiple anxiety disorders, depression, or a history of substance abuse will be discussed with a view to choosing the appropriate management strategy. Treatment options will be reviewed.

Differential subtyping of depression.

We studied a group of patients with depression divided into subtypes of non-chronic major depression, chronic major depression, and pure dysthymia. The purpose of this study was to determine if clinical and family history factors separated these types of depression. We reviewed records from semi-structured clinical interviews and abstracted data regarding factors that might differentiate these three depressive subtypes. In general we found what might be predicted from the definitions of dysthymia versus major depression, that is, ratings for severity of depression were lower for dysthymic patients as compared to patients with non-chronic or chronic major depression. We also found lower ratings for social functioning (GASF) for dysthymic patients as compared to the other depressive subtypes. Our study does not provide data to sufficiently separate these three subtypes. However, in the course of reviewing the literature on this topic, very few studies have separated patients into these distinct depressive subtypes. Further studies are needed to indicate if these subtypes can be meaningfully separated.

A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression.

BACKGROUND: Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. METHODS: We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments. RESULTS: Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group. (P<0.001 for both comparisons). Among the 519 subjects who completed the study, the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group, as compared with 85 percent in the combined-treatment group (P<0.001 for both comparisons). The rates of withdrawal were similar in the three groups. Adverse events in the nefazodone group were consistent with the known side effects of the drug (e.g., headache, somnolence, dry mouth, nausea, and dizziness). CONCLUSIONS: Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone.

Optimizing lithium treatment.

The purpose of this article is to discuss treatment of side effects that can occur during lithium therapy. Side effects from lithium are common but generally benign. For this article, I have divided the side effects into those that occur early, those that are late appearing, side effects related to drug interactions, and lithium toxicity. Side effects can decrease compliance. Lithium is a very effective drug for the stabilization of mood disorder in bipolar patients. Since side effects can affect compliance, recognition and treatment of early and late-appearing side effects are important aspects of lithium pharmacotherapy.

Relationship of childhood physical and sexual abuse to adult bipolar disorder.

OBJECTIVES: To characterize whether adult depressives with either bipolar or unipolar disorder differ in the prevalence of childhood sexual or physical abuse. METHOD: The investigators reviewed data from patients who were evaluated over a 2-year period by a semi-structured clinical interview. In total, 333 cases with a bipolar or unipolar diagnosis were included in the present study. RESULTS: A childhood history of abuse, in particular sexual abuse, was significantly more frequent in bipolar subjects compared with unipolar subjects. Consistent with previous studies, women reported higher rates of sexual abuse than men, although no interaction by diagnosis was shown. Sexual abuse incidence in male samples was markedly dissimilar, with male bipolar subjects demonstrating a significantly increased rate of sexual abuse and combined sexual and physical abuse compared with unipolar male subjects. CONCLUSION: The increased incidence of sexual abuse in women supports growing evidence of gender differences in sexual abuse among adult depressives. In contrast to literature reports, the finding that male bipolar patients have significantly increased rates of sexual abuse histories suggests differences in psychiatric depressive subgroups. This result may reflect the particular characteristics of our cohort (treatment resistant, privately insured, and educated). Further work will aid in characterizing sexual abuse prevalence in other male bipolar samples.

Relationship between borderline personality disorder and Axis I diagnosis in severity of depression and anxiety.

BACKGROUND: This study tested the hypothesis that subjects with borderline personality disorder irrespective of the presence or absence of an Axis I mood or anxiety disorder would exhibit greater severity of depression and anxiety than subjects with either a personality disorder other than borderline personality disorder or no personality disorder. METHOD: Two hundred eighty-three subjects from an outpatient psychiatry clinic were administered the following assessments: the Structured Clinical Interview for DSM-III-R (SCID) for Axes I and II, the Hamilton Rating Scales for Depression and Anxiety, the Beck Depression Inventory, and the Spielberger State-Trait Anxiety Inventory. Subjects were categorized into borderline personality disorder, other personality disorder, and no personality disorder categories and into present versus absent categories on Axis I diagnosis of depression and of anxiety. A 2-factor multiple analysis of variance compared personality disorder status and Axis I diagnosis on severity of depression by observer rating and self-report. The analysis was repeated for anxiety. RESULTS: As hypothesized, significant main effects were found for borderline personality disorder and for both depression and anxiety. Subjects with borderline personality disorder showed greater severity on both depression and anxiety rating scales than did patients with another personality disorder, who showed greater severity than did patients with no personality disorder. Axis I diagnosis was also associated with greater severity on depression or anxiety rating scales. These differences were found for both observer ratings and self-report. An interaction was also found for depression: Subjects with borderline personality disorder but without an Axis I diagnosis of depression rated themselves as more severely depressed on the Beck Depression Inventory than did subjects with another or no personality disorder who also had an Axis I diagnosis of depression. CONCLUSION: Implications from the study are discussed including the need to assess for borderline personality disorder in research studies of depression and anxiety and to integrate treatments for borderline personality disorder into depression and anxiety treatment to maximize clinical outcomes.

Duration of periods of euthymia in patients with dysthymic disorder.

OBJECTIVE: The purpose of this study was to assess the duration of periods of euthymia in patients with dysthymia. METHOD: All patients with dysthymia who came to the Center for Anxiety and Depression over a 10-month period (N = 22) were interviewed by the author regarding the duration of their euthymic episodes. RESULTS: The 22 patients with dysthymia reported euthymic periods from 2 to 30 days (mean = 8.0 days, SD = 6.6). CONCLUSIONS: The euthymic period of up to 2 months that is specified in DSM-IV for dysthymic disorder might confound the results of clinical trials. Data from additional groups of dysthymic patients would be useful when considering this issue for DSM-V.

Dysthymic disorder: treatment with mirtazapine.

Dysthymic disorder is a form of chronic depression which often has its onset in childhood or adolescence and is generally persistent throughout life. Although originally hypothesized to be preferentially treated with psychotherapy, recent pharmacological studies support the use of antidepressants to treat patients with dysthymic disorder. Mirtazapine is an antidepressant which has been recently released on the U.S. market. We studied the effects of 15 to 45 mg of mirtazapine in 15 patients with dysthymic disorder on an open label basis over a 10-week period. Four patients discontinued treatment because of sedation. Mirtazapine was effective and well tolerated in the remaining patients.

Treatment of dysthymic disorder.

Recent studies support the use of pharmacotherapy in the treatment of dysthymic disorder. This article reviews the relationship of the definition of dysthymic disorder to clinical treatment studies and discusses the treatment of dysthymic disorder with pharmacotherapy (with special emphasis on the use of fluoxetine) and psychotherapy.

The issue of comorbidity in the treatment of panic.

Both depression and panic disorder are found commonly in community surveys and it is not unexpected that there should be a co-occurrence of these disorders in some patients. However, recent data suggest that there is a greater clustering of depression among panic disorder patients and panic disorder among depressed patients than one might expect by chance alone. For example, further analysis of data from the National Comorbidity Survey indicates that there is a history of major depression in 55.6% of subjects with lifetime panic disorder and that 21.6 % of depressed patients experience a panic attack at some time in their lives. The high incidence of comorbidity of panic and major depressive disorders emphasizes the value of pharmacotherapy with a broad-spectrum agent that can treat the symptoms of comorbid psychiatric disorders effectively. Of the therapeutic options available, there is mounting evidence that selective serotonin reuptake inhibitors (SSRIs) represent reasonable monotherapy for patients with comorbid depression and panic disorder, based on the equivalent efficacy and improved side-effect profiles compared with other classes of antidepressant. The clinical relevance of differences in the pharmacokinetic and clinical profiles of SSRIs have been discussed in the context of treatment strategies for the patient with comorbid depression and panic disorder.

A prospective safety surveillance study for bupropion sustained-release in the treatment of depression.

BACKGROUND: This prospective 105-site study was conducted to determine the rate of seizures and other serious adverse experiences associated with the therapeutic use of the sustained-release formulation of bupropion (bupropion SR). METHOD: 3100 patients with a DSM-III-R diagnosis of depression without a current or past diagnosis of an eating disorder and with no personal or family history of seizure disorders were treated for up to 8 weeks with bupropion SR in an open-label study. Dosing was initiated at 50 mg b.i.d. and increased to a maximum of 150 mg b.i.d. unless not tolerated. Patients had the option to continue treatment with bupropion SR (50 mg b.i.d. to 150 mg b.i.d.) in a continuation phase lasting up to 1 year. During the acute and continuation phases, patients were evaluated for the occurrence of seizures and other serious adverse experiences. Clinical response to and tolerability of bupropion SR were also evaluated. RESULTS: Three patients each experienced a seizure associated with the therapeutic use of bupropion SR during the acute and continuation phases combined. The observed seizure rate during the 8-week acute phase was 2 seizures in 3094 evaluable patients, or 0.06%. The observed seizure rate for the acute and continuation phases combined was 3 seizures in 3094 patients, or 0.10%. Survival analysis yielded a cumulative seizure rate of 0.08% for the acute phase and 0.15% for both phases combined. Two patients who intentionally overdosed with bupropion SR also experienced seizures; however, these events were not included in calculations of the overall seizure rate. Therapeutic doses of bupropion SR were well tolerated and clinically efficacious. CONCLUSION: The therapeutic use of bupropion SR at total daily doses up to 300 mg/day in depressed patients without predisposition to seizures is associated with a seizure rate that is well within the range observed with other marketed antidepressants.

Bipolar disorders in DSM-IV: impact of inclusion of rapid cycling as a course modifier.

In this paper, we review the process for inclusion of rapid cycling as a course modifier to bipolar disorders in DSM-IV. This process involved definition of bipolar II disorder, delineating the duration of manic episode for bipolar I disorder, and clarification of the diagnosis of cyclothymic disorder and mixed mania.