At the 2015 meeting of the International Society for Bipolar Disorders, researcher John Geddes presented an important study showing in inadequate responders to quetiapine that compared to adding placebo, adding the anticonvulsant lamotrigine to their treatment improved depression rapidly and lastingly. Some psychiatrists have been prescribing this combination to patients for some time, but this is the first formal clinical trial documenting its efficacy. The article was published online in December in the journal Lancet Psychiatry.
Researcher Guy Goodwin described details of the study, called CEQUEL, at the meeting. It included 202 patients with bipolar I or II disorder who required treatment for a depressive episode. Participants who did not respond completely to 14 days of treatment with quetiapine were prescribed either an additional dose of lamotrigine or a placebo. Lamotrigine was very slowly titrated up to maximum doses of 200mg/day. Its antidepressant effects were striking. They began early and persisted for 50 weeks. (The published article covers only the first 12 weeks.) Response rates for the combination of quetiapine and lamotrigine were 52%, compared to 22% for quetiapine alone. Remission rates were 35% for quetiapine and lamotrigine and 12% for quetiapine alone.
Folic acid interaction
Another part of the study assessed whether folic acid supplements could improve outcomes, but in fact they did the opposite, reversing the benefits of adding lamotrigine. Geddes did not have an explanation for why this might be the case. Lamotrigine can inhibit folate metabolism, and it had been thought that adding folate would be useful. Until further data are gathered on folate augmentation in patients taking the combination of lamotrigine and quetiapine, folate should be used cautiously if at all in these patients.
Possible combination with lithium
In Goodwin’s talk, he also noted lithium’s potential to lower suicide rates, premature mortality, and cognitive impairment, and to increase hippocampal and cortical volume.
Since lamotrigine was shown to potentiate the antidepressant effects of lithium in a study by Van der Loos and colleagues, and quetiapine is approved by the Food and Drug Administration for the prevention of depression as an adjunct to lithium (or valproate), there might be theoretical acute and long-term benefits to combining the three: lithium, quetiapine, and lamotrigine.
In a new study of patients with major depressive disorder who did not improve after eight weeks of the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram, the addition of the atypical antipsychotic ziprasidone improved their depression more than did placebo. Patients took the combination of escitalopram (20mg/day on average) and ziprasidone twice a day at doses of 20–80 mg.
This was the first randomized, double-blind placebo controlled trial of ziprasidone as an adjunct treatment for unipolar depression. While ziprasidone was more efficacious than placebo, discontinuation of the study due to intolerance was higher among the patients who received ziprasidone.
Editor’s Note: Two atypical antipsychotics (quetiapine and aripiprazole) have been approved by the Federal Drug Administration for augmentation of antidepressants in unipolar depression. Now there have also been placebo-controlled positive trials of two others (ziprasidone and cariprazine).
These findings are of particular interest as the studies of ziprasidone monotherapy in bipolar depression not only failed, but response to ziprasidone and placebo was virtually identical (and negligible).
Transcranial Direct Current Stimulation Plus Zoloft Has Better Antidepressant Effects Than Either Treatment Alone
Transcranial direct current stimulation (tDCS), in which a barely perceptible level of electrical current is applied directly from one side of a patient’s scalp to the other, is a promising treatment for patients with tought-to-treat depression. A 2013 study by Brunoni et al. in JAMA Psychiatry examined whether combined treatment using tDCS and the selective-serotonin reuptake inhibitor (SSRI) antidepressant sertraline (Zoloft) would be a safe and effective treatment for unipolar depression. The combination was better than either treatment alone and better than placebo.
The six-week study used what is called a 2×2 factorial design, in which 120 patients with unipolar depression received either 50 mg/day of sertraline or placebo and also received either real tDCS or a sham procedure. The tDCS was administered in twelve 30-minute sessions, one per day Monday through Friday during the first two weeks, followed by one every other week. TDCS consists of an anodal (positive) and cathodal (negative) current placed at particular positions on the head. This study used 2 microamps of anodal left/cathodal right prefrontal stimulation for the tDCS treatment.
While the combination of sertraline and tDCS was significantly better than all three other treatment options (sertraline plus sham procedure, placebo plus tDCS, and placebo plus sham procedure), sertraline by itself and tDCS by itself resulted in similar efficacies. However, TDCS by itself was also significantly better than placebo, while sertraline by itself was not.
Side effects among the different treatment options were similar, except those who received tDCS had more scalp redness. There were seven instances of patients developing mania or hypomania during the study, five of which occurred in the combined tDCS and sertraline treatment group, higher than the 1–2% rate that would be expected in a study of unipolar depression.
The combination of the anti-anxiety drug buspirone (trade name Buspar) and melatonin, a hormone that regulates cycles of sleep and waking, may be effective for depression. Researcher Maurizio Fava and other researchers at Massachusetts General Hospital report that low-dose buspirone (e.g. 15 mg/day) combined with a 3 mg dose of melatonin produced significant antidepressant effects in a six-week study of patients with unipolar depression.
While buspirone is not a potent antidepressant at low doses, the combination of buspirone and melatonin exerted significant effects, leading to better antidepressant response than did either placebo or 15 mg of buspirone alone. Another benefit of the combination is that the low dose of buspirone minimizes side effects.
Buspirone is a serotonin 5HT1A receptor partial agonist, meaning that it produces weak activity at this serotonin receptor, but does not allow it to get overstimulated.
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.