Anger, Aggression Reactivity in Depression May Signal Risk for Converting to Bipolar Disorder

Patients who have depression and frequently experience bouts of anger may have an increased risk of developing bipolar disorder, a study in Depression & Anxiety has found. The study also found a link between aggression reactivity—aggressive behavior in response to feeling threatened, provoked, or frustrated—and conversion to bipolar disorder.

Rahele Mesbah, M.Sc., of Leiden University Medical Center in Leiden, The Netherlands, and colleagues analyzed data from 1,585 people with depression who participated in the Netherlands Study of Depression and Anxiety (NSDA), a longitudinal study of adults aged 18 to 65 years. Four years into their participation, people in the NSDA completed questionnaires about trait anger (tendency toward anger as a personality trait), aggression reactivity, anger attacks, and personality traits associated with greater amounts of anger. NSDA participants were also evaluated using the Composite International Diagnostic Interview at two, four, six, and nine years of follow-up.

At the end of four years, 77 people converted to bipolar disorder, 349 had current depressive disorder, and 1,159 had remitted depressive disorder. Those who converted to bipolar disorder had the highest levels of trait anger and aggression reactivity. They also had the greatest prevalence of anger attacks, antisocial personality traits, and borderline personality traits.

In a separate analysis, this time including 1,744 people with depression in the NSDA who had nine years of follow-up, the researchers found that aggression reactivity predicted incident hypomania and thus conversion to bipolar disorder.

“Feelings of anger might be an important target for early recognition of illness and intervention in BD [bipolar disorder],” Mesbah and colleagues wrote. “Increased feelings of anger in unipolar patients in combination with some other known clinical characteristics, such as multiple brief depressed episodes, a lack of response to antidepressants, [or] a family history of [bipolar disorder] might help to signal an upcoming conversion to [bipolar disorder].”

For related information, see the American Journal of Psychiatry article “Early Intervention in Bipolar Disorder.”

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Light Therapy for Bipolar Depression Poses Minimal Risk of Mania Switching

Light therapy has been shown to be an effective treatment for bipolar depression, but there have been concerns that light therapy might increase the risk of triggering mania or hypomania in patients with bipolar disorder.

A meta-analysis published in the March issue of Psychiatry Research suggests that the risks of switching into mania during light therapy are quite low—roughly the same risk of switching among patients with bipolar disorder taking placebo medications in clinical studies.

Francesco Benedetti, M.D., of the Scientific Institute Ospedale San Raffaele in Milano, Italy, analyzed data from 41 studies evaluating the effects of light therapy on patients with bipolar depression. Of the 799 patients included in these studies, only 7 (0.9%) switched into mania and 11 (1.4%) switched into hypomania. Three of the patients who switched into mania had rapid-cycling bipolar disorder, which the authors noted is a risk factor for switching.

Further analysis of the data showed that the risk of switching was independent of the treatment design (for example, light intensity or time of day of treatment). However, the rate of switching varied based on how the investigators screened for mania symptoms. Among studies that used a mental state examination to assess mania, the identified switching incidence was 0.8%, while in studies that used clinical rating scales, the incidence was 3%.

Benedetti noted that the 3% risk of a patient switching into mania following light therapy is still a lower risk than most other treatment options. Current estimates suggest mania emerges in about 4% of bipolar patients taking a placebo medication, 6% to 8% of unipolar depression patients taking antidepressants, and 15% to 40% of bipolar depression patients taking antidepressants.

Benedetti cautioned that since the 41 studies included in the meta-analysis were quite different in their protocols, more well-designed trials are required to investigate the optimal intensity and frequency of light therapy for bipolar depression. “Overall, these observations do not justify specific safety concerns for the risk of manic switches when using this treatment option in patients with bipolar depression,” he concluded.

To read more about this topic, see the Psychiatric News article “Adjunctive Light Therapy Found Effective for Bipolar Depression.”

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Mixed Depression May Be More Common Than Previously Thought

A study published today in AJP in Advance suggests the presence of “mixed features” (concurrent manic and depressive symptoms) is more common in patients with bipolar disorder—particularly in women—than may be diagnosed using the criteria in DSM-5.

“Our results raise the possibility that relaxing the diagnostic criteria for the mixed features specifier ... may yield greater sensitivity for identifying patients with mixed depression,” Shefali Miller, M.D., a clinical assistant professor of psychiatry and behavioral sciences at Stanford University, and colleagues wrote.

The researchers analyzed the outcomes of 907 adult outpatients with bipolar disorder across 14,310 visits between 1995 and 2002. At each visit, mania and depression symptoms were assessed using the Inventory of Depressive Symptomatology–Clinician-Rated Version (IDS-C) and the Young Mania Rating Scale (YMRS). Patients with an IDS-C score of greater or equal to 15 and a YMRS score between 2 and 12 at the same visit were classified as having mixed depression.

The presence of mixed depression was observed in 2,139 visits (14.9% of total) and among 584 patients (64.4% of total). Those classified as having one or more mixed depression visits also had more symptomatic visits and fewer non-depressed visits compared with those with no mixed depression visits. DSM-5-based definitions of mixed depression (ranging from narrower definitions requiring three or more nonoverlapping YMRS items concurrent with an IDS-C score of greater or equal to 15, to broader definitions requiring two or more nonoverlapping YMRS items) yielded lower mixed depression prevalence rates (6.3% and 10.8% of visits, respectively).

The authors also found that women were significantly more likely than men to experience subthreshold hypomania during visits with depression (40.7% compared with 34.4%). In both groups, however, visits with mixed depression were associated with higher scores on all individual YMRS items, notably language-thought disorder, speech, and increased motor activity—three YMRS items that a previous study suggested were predictive of antidepressant treatment–emergent mania.

“The present findings suggest that the presence of mixed symptoms during depression visits may signal heightened risk for antidepressant-induced mania, warranting particular caution in clinical decision making,” the authors wrote.

For more on the study and the significance of the findings, see a related video by American Journal of Psychiatry Deputy Editor A. John Rush, M.D.

For other related information, see the Psychiatric News article “Lurasidone Effective in Treating Depression With Mixed Features.”

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Lurasidone Found to Be Safe, Effective in Patients With Mixed Forms of Major Depression

Once daily treatment with lurasidone for six weeks decreased depressive and manic symptoms in patients with mixed forms of major depression with limited adverse effects, according to a study published Tuesday in AJP in Advance.

A growing body of evidence suggests that manic symptoms below the threshold for hypomania (mixed features) are common in individuals with major depressive disorder. Little is known of the best treatment options for this form of depression, but some clinical trials have suggested that standard antidepressants may be ineffective for this condition and associated with potential treatment-related complications, including suicidal ideation and behavior, manic switch, agitation, and impulsivity.

For the current study, researchers from Stanford University and Sunovion Pharmaceuticals randomly assigned patients aged 18-75 with a major depressive disorder (based on DSM-IV-TR criteria) who also reported two to three manic symptoms for at least two weeks prior to screening to take lurasidone (20-60 mg) or placebo daily for six weeks.

Lurasidone significantly improved depressive symptoms compared with placebo, as indicated by changes from baseline in Montgomery-Åsberg Depression Rating Scale score and the Clinical Global Impressions severity subscale score. Manic symptoms were also significantly improved in the lurasidone group, and treatment with lurasidone was associated with significant improvement both in anxiety symptoms and in patient-reported functional impairment. Nausea (6.4% and 2.0% in the lurasidone and placebo groups, respectively) and somnolence (5.5% and 1.0%) were the most common adverse events reported by the study participants.

“There is a pressing need for evidence-based treatments of major depressive disorder presenting with subthreshold hypomanic symptoms (mixed features), especially given its complex course and associated morbidity,” the study authors wrote. “Treatment with lurasidone was well tolerated, with a favorable benefit-risk profile in this difficult-to-treat clinical population. Further investigation is needed to determine whether these findings are applicable to other agents in the atypical antipsychotic class.”

For related information on lurasidone’s effectiveness in treating bipolar I depression, see the Psychiatric News article “Data Released Backing Lurasidone’s New Indication.”

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