A 2012 study by Kemp et al. in the journal Bipolar Disorders found that lamotrigine added to combination treatment with lithium and valproate was no more effective than placebo in patients with rapid cycling bipolar disorder. Only 14% (19 out of 133) of rapid cycling patients stabilized upon initial treatment with the open combination of lithium and valproate, a startlingly low rate. In the next phase of the study, 49 patients who were not stabilized were given adjunctive treatment with either lamotrigine (n=23) or placebo (n=26) on a double-blind basis, but no significant difference was observed.
Editor’s Note: This study has two pieces of not-so-good news. The first is that it was so difficult to stabilize these patients with rapid cycling bipolar disorder. The second is that the add-on of lamotrigine, which is highly effective in the prevention of depressions in bipolar disorder, was in this case no more effective than placebo.
This study again demonstrates that rapid cycling bipolar disorder is difficult to treat, and even the use of three proven mood stabilizers in combination is not always effective. Many doctors would recommend an atypical antipsychotic as the next clinical option.
In an open study of bipolar disorder treatment, Shefali Srivastava, Terence Ketter and colleagues at Stanford University evaluated ziprasidone as an aid to patients unresponsive to other medications. This study was part of the multi-center research program Systematic Treatment and Evaluation Program for Bipolar Disorder, or STEP-BD. During naturalistic treatment, ziprasidone was added to an average of 3.6 other psychotropic medications and 1.2 other nonpsychotropic medications patients had already been prescribed. The researchers found substantial improvement in mood with ziprasidone, particularly in the patients who had symptomatic levels of depression at baseline. The research team also observed a mean weight decrease from 195 + 50lbs at baseline to 183 + 47lbs at the final visit, with 34.3% of the patients achieving at least a 7% weight loss with ziprasidone.
Mean trial duration was 860 + 700 days, with no subsequent psychotropic agents added in 51.2% of the patients who had a mean trial duration of 221 + 272 days. Ziprasidone was discontinued in 57.3% of the 82 trials after a mean of 208 + 364 days. This was due to side effects in 26.8% of the participants and due to inefficacy for mood in 23.2%.
The investigators concluded that in bipolar patients treated naturalistically with complex pharmacotherapy, ziprasidone decreased overall bipolar illness severity, was helpful in patients with substantial depression at baseline, and also yielded clinically significant weight loss in about one-third of the patients.
Editor’s note: These data are notable because they support ziprasidone’s pattern of weight neutrality and because of the overall improvement in mood symptomatology the drug brought about. Read more
Psychotherapy and psychoeducational approaches, long-term psychopharmacology, and combination therapy all play a role in preventing recurrent mood episodes.
Psychotherapeutic and Psychoeducational Approaches Are Critical
A number of studies presented at the 4th Biennial Conference of the International Society for Bipolar Disorders in Sao Paulo, Brazil in March indicated that cognitive-behavioral therapy (CBT) and individual and group psychoeducational approaches enhance both short- and long-term outcomes for patients with bipolar illness. These studies add to an already substantial literature that shows that focused psychotherapies (such as cognitive/behavioral, interpersonal, and social rhythms therapies) and psychoeducation are superior to treatment as usual.
These therapies can provide a variety of approaches to stress management and reduction, and can enhance family and interpersonal communication. Another way these focused psychotherapeutic approaches help patients is by demonstrating the benefits of effective long-term preventive treatment and encouraging its consistent use.
Without consistent prophylactic treatment, patients are at high risk for recurrences and their subsequent psychosocial and neurobiological consequences. Greater number of prior episodes is associated with an increased risk of psychosocial dysfunction, treatment resistance, cognitive dysfunction, medical comorbidities, and even dementia in old age.
After the jump: preventive psychopharmacology and combination therapy. Read more
The two main classes of drugs for the treatment of Alzheimer’s disease currently include cholinesterase inhibitors, which increase brain acetylcholine levels, and memantine (Namenda), which is a partial blocker of glutamate receptors. Treating patients with both types of drugs in combination may help their cognitive functioning.
The brains of patients with Alzheimer’s are deficient in acetylcholine. Acetylcholinesterase breaks down acetylcholine, so the first class of Alzheimer’s drugs inhibits these esterases and makes more acetylcholine available.
Memantine works a different way. Glutamate is the major excitatory neurotransmitter in the brain. Excesses of glutamate may be toxic to cells, so memantine’s ability to partially block glutamate receptors may explain the drug’s effectiveness in Alzheimer’s.
In a study comparing valproate monotherapy with the combination of lamotrigine and divalproex (Valproate) extended release (ER), the combination appeared more effective in bipolar depression. At the American College of Neuropsychopharmacology meeting in December 2009, Vivek Singh, Charles Bowen, Richard Weisler, and colleagues from The University of California, San Diego reported on the randomized, double-blind, eight-month maintenance study of bipolar depressed patients.
Patients who could be stabilized for two consecutive weeks on the combination treatment of both lamotrigine and divalproex were then randomized to either lamotrigine alone or the combination for the duration of the study. Most of the data collected about these 87 subjects favored the treatment with the combination (lamotrigine plus divalproex) compared with lamotrigine alone. Combination therapy was superior for manic symptomatology and resulted in lower rates of unanticipated worsening of depression (greater than 20 points on the Montgomery-Asberg depression rating scale (MADRS)) that led to termination from the study than lamotrigine monotherapy did.
Generalized anxiety disorder (GAD) is a prevalent illness often associated with considerable discomfort and dysfunction. It often co-occurs with bipolar disorder. Traditional treatments of the primary syndrome (occurring in the absence of bipolar disorder) involve serotonin-selective antidepressants and serotonin-noradrenergic reuptake inhibitors such as venlafaxine (Effexor) or duloxitine (Cymbalta). While these are often useful and lead to considerable improvement, they often do not lead to full remission of somatic or accompanying symptoms of insomnia.
Alternative treatment possibilities include the anticonvulsant pregabalin (Lyrica), which has been found effective in four placebo-controlled studies in GAD. A poster presentation by Joshi et al. at the American Psychiatric Association meeting in San Francisco in May 2009 also reported that pregabalin was more effective in reducing sleep disturbance than venlafaxine. Pregabaline is FDA-approved for seizures and fibromyalgia, but not for GAD or pain syndromes. Another treatment possibility is quetiapine (Seroquel), where not only have there been positive efficacy in placebo-controlled studies of patients with GAD, but the patients also experienced improvement in sleep.