Mood Stabilizers with Atypical Antipsychotics Reduce Relapses Compared to Mood Stabilizers Alone or with Typical Antipsychotics
An Israeli study reports that treatment with mood stabilizers and atypical antipsychotics reduces bipolar relapses compared to treatment with mood stabilizers alone or mood stabilizers combined with typical antipsychotics. The study, by Eldar Hochman and colleagues in the journal Bipolar Disorders, compared one-year hospitalization rates after patients with bipolar disorder were discharged from the hospital following a manic episode. All of the 201 discharged patients were prescribed a mood stabilizer (lithium or valproate), and some were also prescribed an antipsychotic, either atypical or typical.
Those participants who received the combination of a mood stabilizer and an atypical antipsychotic had re-hospitalization rates of 6.3% compared to 24.3% of those who received mood stabilizers alone and 20.6% of those who received mood stabilizers with a typical antipsychotic.
While the study did not determine which treatment is best for ongoing maintenance treatment of bipolar disorder, it does suggest that the combination of mood stabilizers and atypical antipsychotics can reduce hospitalizations during the one-year period following a manic episode.
The timeframe during which recovery and recurrence occur in people with a first episode of mania are somewhat variable. A meta-analysis by Andréanne Gignac and colleagues published in the Journal of Clinical Psychiatry in 2015 offers some new information. The meta-analysis included eight studies with a total of 734 participants in a first episode of mania. Syndromal recovery rates (when patients no longer met diagnostic criteria for bipolar disorder) were 77.4% at six months after first episode of mania and 84.2% at one year after. However, some symptoms lingered, and only 62.1% of patients reached a period of symptomatic recovery within one year.
Recurrence rates were 25.7% within six months, 41.0% within one year, and 59.7% by four years. Those who were younger at the time of the first episode were at higher risk for relapse within one year.
Editor’s Note: On the positive side, most recovered, but on the negative side, at one year, 60% remained symptomatic and 40% had a recurrence. What is not clear is how intensively patients were treated and monitored. The main message of this study is that a first episode of mania is not trivial and deservces concerted acute and long-term treatment. When expert multimodal treatment is given results are vastly more superior than treatment as usual (Kessing et al. British Journal of Psychiatry 2013).
Danish researcher Lars Kessing recently performed the first randomized controlled study of the efficacy of early intervention in bipolar disorder.
Patients who had been hospitalized for a first episode of mania were randomly assigned to two years of treatment in a specialized clinic versus two years with treatment as usual in the community (the control condition). The researchers predicted that then specialized clinic would decrease subsequent hospitalizations, and increase adherence to medication and patient satisfaction compared to treatment as usual over the subsequent six years.
Treatment at the special clinic began with a phase of post-hospitalization settling in, followed by psychoeducation (15 weeks of 1 session/week). Emphasis was placed on the recognition of breakthrough symptoms—early warning signals of an impending mood episode.
All three outcomes were better in the group who were treated at the specialized clinic than in control group who received treatment as usual. Hospitalizations were reduced 40%, medication compliance was enhanced, and patients were more satisfied. Patients younger than age 36 showed greater improvement and greater differences from the control group than were seen among older patients.
One striking observation was that the difference observed after patients had spent two years in the specialized clinic compared to the control group persisted and grew over the following four years, even though these patients left the specialized clinic after the first two years.
The specialized clinic was not only successful, but was also cost-effective. Clinic patient care led to a savings of €3,194 per patient. The costs for clinic patients were 11% of those for control patients.
Editor’s Note: We already know that treatment delay is related to poor outcome. (See article by this editor Robert Post et al. in the Journal of Clinical Psychiatry in 2010.) This study is groundbreaking in demonstrating that the quality of care in a specialized clinic has enormous personal, societal, and financial benefits, and can render the course of illness more benign over a sustained period of at least 6 years.
This means that a revolution in the care and treatment of patients with bipolar disorder is needed throughout the world, but especially in the US, where the typical treatment paradigm is as bad or worse than the treatment as usual condition in Kessing’s Danish study. When patients are discharged from the hospital, they are immediately at increased risk for relapses and, most alarmingly, at 200-fold increased risk of suicide. This post-hospitalization gap in treatment between episodes needs to be better managed. Transitional care is rarely handled well, psychoeducation is rarely given for a sufficient duration, therapy is often unavailable, and medication non-compliance is high. These factors lead to increased illness, re-hospitalizations, and skyrocketing personal and societal costs. Moreover, only 20% of bipolar patients identified in epidemiological studies in the US are in any kind of treatment.
Treatment guidelines must be changed to better address these issues. A first episode of mania should trigger a cascade of sequential treatments: Read more
George Koob, the new director of the National Institute for Alcohol Abuse and Alcoholism (NIAAA), showed that animals with extended access to self-administered abuse substances like cocaine or morphine will escalate the amount of drug they self-administer. When the drug is no longer available starting after a delay of one to two weeks, the number of times they press a lever in the presence of a cue previously associated with drug availability progressively increases over a period of one to two months (even through no drug is available). This is called incubation and reflects a measure of “craving” or relapse potential.
This incubation effect, or increasing degree of craving for a drug, is also seen clinically in people who are heavy drug users and then achieve abstinence or are incarcerated and have a period of forced abstinence. As the duration of abstinence increases, they experience an increased proneness to relapse.
Dynorphin is a psychomimetic opiate peptide that is produced in the brain and causes anxiety and dysphoria when it is given to humans. While opiates like morphine and heroin that produce euphoria and antipain effects act at a mu opiate receptor, dynorphin acts at a kappa opiate receptor. Chronic cocaine use gradually increases levels of dynorphin in the brains of addicts and also increases kappa receptors, thus converting what is often initially a euphoric drug experience into an anxiety-producing and dysphoric one.
If kappa receptors are blocked, the incubation effects during abstinence described above do not occur, and presumably addicts would be less relapse-prone. No kappa antagonist is currently available for human use, but if one combines buprenorphine (a mixed opiate agonist/antagonist) with naloxone or naltrexone (which selectively block the mu opiate receptors), one would in effect have a kappa receptor antagonist. Koob showed that this drug combination could prevent the incubation effects in abstinent animals. Further study might lead to advances in the treatment of addition in humans.
At a symposium on early-onset depression at the 2013 meeting of the American Academy of Child and Adolescent Psychiatry, Graham Emslie of the University of Texas Southwestern Medical Center discussed the role of cognitive behavioral therapy in the long-term treatment of child-and adolescent-onset unipolar depression.
In Emslie’s research, the combination of the antidepressant fluoxetine and cognitive behavioral therapy reduced depressive relapses in children. Using the two treatments together did not speed onset of antidepressant response compared to fluoxetine alone, but once children responded to the medication, the addition of cognitive behavioral therapy reduced relapses over the next year compared to fluoxetine alone (even though the cognitive behavioral therapy ended after the first six months).
Emslie likened the use of cognitive behavioral therapy to the course of rehabilitation that often follows a major surgery and is meant to sustain or enhance the good effects of surgery. Getting patients to full remission (well and with no residual symptoms) was the key to staying well.
Electroconvulsive therapy (ECT) is an effective treatment for patients with treatment-resistant depression, but still many patients relapse after the treatment. Medications can prolong the period of remission, but even so, relapse rates have increased in recent decades (probably at least partly because ECT was once a standard initial treatment but is now only used with those patients with the most difficult-to-treat illnesses.) A 2013 meta-analysis by Jelovac et al. in Neuropsychopharmacology reviewed existing research on relapse and which medications might be able to best prolong remission after ECT.
The researchers analyzed 32 studies that each included at least 2 years of followup. In studies from the recent era in which patients received continuation treatment with medication following ECT, 51.1% of patients relapsed within a year, and the majority of those (37.7%) relapsed within the first 6 months after ECT. Among patients treated with continuation ECT, a similar proportion (37.2%) also relapsed within 6 months of the initial ECT treatment. In randomized controlled trials, treatment with antidepressants with or without lithium following ECT halved the rate of relapse within 6 months compared to placebo.
Even with continuing intermittent ECT treatment, risk of relapse remains high, especially within the first 6 months. The authors concluded that maintenance of wellbeing following ECT must be improved.
Editor’s Note: One possibility for prolonging remission is the more intensive continuation regimen using right unilateral ultrabrief pulse ECT suggested by Nordenskjöld et al. in the Journal of ECT in 2013. Continuation treatment with a combination of ECT and medication resulted in 6-month relapse rates of 29% (compared to 54% with medication alone) and one-year relapse rates of 32% (compared to 61%).
A 2013 study by Prudic et al. in the Journal of Electro-convulsive Therapy reveals some good and some not-so-good news about ECT. The good news about ECT is that it produced moderate acute remission rates. In this randomized study of ECT treatment, improvement rates were better when patients received right unilateral (RUL) ultra-brief pulse at high doses (6 times a patient’s seizure threshold) than with bilateral (BL) pulse at low doses (1.5 times the patient’s seizure threshold). RUL also has fewer cognitive side effects than BL.
Prudic also found that these acute remission rates were best when antidepressant treatment was begun at the same time as ECT rather than after the end of ECT treatment.
Unfortunately, a previous study by Prudic et al. showed that relapse rates after ECT remain high. Two-thirds of patients relapse in the first six months after ECT. Half of patients who receive antidepressant treatment following ECT relapse within the first six months after their last ECT treatment. Twenty to forty percent relapse in the first month after their last ECT treatment.
In the current study, timing and likelihood of relapse was independent of whether antidepressant treatment was started at the outset of ECT or after the end of ECT. Relapse also did not depend on which pharmacological treatments are used (nortriptyine plus lithium versus venlafaxine plus lithium).
Older patients (average age 55) did better—they relapsed less often than patients with an average age of 45. Patients with unipolar and bipolar depression did not differ in relapse rates.
Previous history of illness did affect relapse. The number of prior antidepressant trials a patient had tried for a current depressive episode (a measure of treatment resistance) was related to how fast they relapsed on follow-up pharmacotherapy after receiving ECT (more antidepressant trials was associated with faster relapse).
Other studies have shown that continuation of ECT treatment is not superior to continued treatment with drugs following ECT treatment.
Editor’s Note: ECT works acutely, but too often its effects do not last long, even with intensive continuation treatment with an antidepressant and lithium. Therefore for patients with highly recurrent illness, its usefulness is largely limited to acute emergencies, such as high risk of suicide or medical deterioration.
There are currently no good controlled studies showing how to prevent depressive relapse after remission with ECT using either drug continuation therapy or maintenance ECT. Greater degrees of treatment resistance are associated with lower rates of both acute remission and faster relapse during follow-up pharmacotherapy.
If a patient is going to have ECT, RUL would be recommended over bilateral, because bilateral ECT is associated with decreases in autobiographical memory even after six months, and these deficits are in proportion to the number of bilateral ECT treatments received.
Alternatives to ECT
Other types of brain stimulation treatments could potentially serve as alternatives to ECT. Read more
In naturalistically treated bipolar patients, depression is three times more prevalent than manic symptoms (according to studies by Judd et al., Kupka et al., and Ezquiaga et al.). The occurrence of even residual depression or subsyndromal symptoms can be highly impairing, and is a predictor of increased likelihood for subsequent relapse, according to a poster presented by Gitlin et al. at the American Psychiatric Association meeting in San Francisco in May 2009.
These new data support that of a large number of other investigators who have made similar observations, all indicating the importance of attempting to achieve full remission as a major goal of clinical therapeutics in order to decrease likelihood of relapse. Gitlin’s study further indicated that impairment of quality of life in bipolar patients was closely related to the degree of their subsyndromal symptomatology.