Studies of rodents with depression-like behaviors revealed that the combination of low (sub-therapeutic) doses of lithium and infusions of ketamine produced antidepressant-like effects. Researchers believed this might mean that in humans, lithium might have a unique effect potentiating the effects of ketamine.
In a small study by Mark J. Niciu presented at the 2015 meeting of the Society for Biological Psychiatry, patients with bipolar depression taking lithium or valproate mood stabilizers were given ketamine infusions or control infusions. In the 23 patients taking lithium and the 13 taking valproate, ketamine’s antidepressant effects were significantly better than placebo, but there was no difference between lithium and valproate with regard to these antidepressant effects. These preliminary data in a small number of subjects do not support the proposition that lithium augments the effects of ketamine in depression.
A study currently in progress indicates that the anti-inflammatory COX-2 inhibitor celecoxib (better known as the arthritis treatment Celebrex) may aid in the treatment of bipolar depression. In a panel session on inflammation at the 2015 meeting of the Society of Biological Psychiatry, researcher Angelos Halaris reported results from the first 26 participants.
Participants were taking mood stabilizers for bipolar disorder and became depressed. They received either 20mg/day of the selective serotonin reuptake inhibitor antidepressant escitalopram (Lexapro) plus either 200mg twice a day of celecoxib or placebo for a total of eight weeks. Those participants who received celecoxib showed greater and more rapid reductions in depression symptoms than those who received placebo.
The study will continue, and Halaris and colleagues will also observe whether measures of inflammation in patients’ blood are correlated with the patients’ responsiveness to the combined treatment with escitalopram and celecoxib.
Despite repeated studies, including meta-analyses, showing that antidepressants that work in unipolar depression do not work in bipolar depression as adjuncts to mood stabilizers, antidepressants remain widely used for the treatment of bipolar depression. A recent study of the antidepressant agomelatine has shown that it is not effective in bipolar depression. In patients taking lithium or valproate but still depressed, agomelatine was no better than placebo at reducing depression.
Agomelatine has an unusual mechanism of action (blockade of 5HT-2C receptors and activation of melatonin M1 and M2 receptors) that helps normalize sleep and circadian rhythms, but only in unipolar depression. Until this study by Lakshmi Yatham and colleagues in the British Journal of Psychiatry, it was thought that these properties would make the drug ideal for bipolar depression.
Three atypical antipsychotics are have been approved by the Federal Drug Administration for bipolar depression: quetiapine (Seroquel), lurasidone (Latuda), and the olanzepine-fluoxetine combination Symbyax. These, used alongside mood stabilizers (lithium, valproate, carbamazepine, and lamotrigine) are more effective treatments for bipolar depression. There are other adjunctive treatments that may be helpful, such as the antioxidant N-acetylcysteine, vitamin D3, and folate.
There is increasing evidence that patients with bipolar disorder benefit from special programs or clinics designed to teach them skills to cope with their illness. A 2015 article by Trijntje Y.G. van der Voort and colleagues in the British Journal of Psychiatry evaluated the effectiveness of a Dutch program that provided collaborative care to people with bipolar disorder.
One hundred thirty-eight patients in an outpatient clinic were randomized to receive either treatment as usual or a program of nurse-provided collaborative care that included psychoeducation, problem-solving treatment, systematic relapse prevention contracts, and monitoring of outcomes. These services were managed by mental health nurses. Those patients who received collaborative care had significantly less time with depressive symptoms at the 6-month and 12-month marks, and less severe depressive symptoms at 12 months (all findings with p values less than .01).
There was no significant difference in manic symptoms or treatment adherence. The authors suggest that collaborative care improves treatment for people with bipolar disorder, especially depression, which is most closely linked to impaired quality of life and disability.
Editor’s Note: Given this study and about a dozen others like it, it is time to conclude that psychoeducation and other components of collaborative care noted here are critical to the long-term management of bipolar disorder. Patients and their family members should insist that this be a part of routine care.
In an eight-week study of the drug cariprazine for bipolar depression by Joe Calabrese and colleagues, patients who received 1.5mg/day doses of the drug showed more improvement in their illness and higher remission rates after six weeks than patients who received placebo. Side effects were rare, with mild or moderate akithisia (restless legs) being most common. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors.
At a recent scientific meeting, researcher John Geddes and colleagues reported that compared to adding placebo to the treatment of bipolar depressed patients already receiving the atypical antipsychotic quetiapine, adding the mood stabilizing drug lamotrigine led to significant improvements in their illness. Lamotrigine was slowly titrated to doses of 200mg/day. (Slowly increasing dosage is important because a serious rash is a possible side effect of lamotrigine, occuring in about one in 5,000 individuals exposed.)
Researcher Charles Bowden found in 2000 that adding lamotrigine to valproate improved its effectiveness, as Marc van der Loos found in 2008 with lamotrigine and lithium. Thus it appears that adding lamotrigine to a mood stabilizer or to an atypical antipsychotic like quetiapine is a good second-line option in the treatment of bipolar depression. While lamotrigine is not FDA-approved for the acute treatment of depression, this approach is worthy of consideration, and could be of immediate clinical use. It provides an alternative to adding a unimodal antidepressant, which recent meta-analyses have indicated is not effective and which can increase switches into mania, cycle acceleration, or even treatment resistance in patients with bipolar disorder.
A limited number of atypical antipsychotics are approved by the Federal Drug Administration for the treatment of depression in patients with bipolar disorder. This is important to note, because the widely used traditional antidepressants that are highly effective in unipolar depression are not effective in bipolar depression. Here we review the status of the only three approved drug treatments for bipolar depression (olanzapine, quetiapine, and lurasidone) and highlight data on a promising new atypical antipsychotic, cariprazine.
At the 2014 meeting of the International College of Psychopharmacology, researcher Joseph Calabrese reviewed the efficacy of the latest atypical antipsychotic to receive FDA approval for bipolar depression, lurasidone. In monotherapy, both low (20–60mg/day) and high doses (80–120mg/day) showed higher response rates (53% and 51%, respectively) than placebo (30%). When added to either lithium or valproate, lurasidone response (57%) again exceeded that of placebo (42%). Calabrese also indicated that all of the other secondary outcome measures were also statistically significant, including score on the Clinical Global Impressions scale for bipolar disorder, time to response, percentage of remitters, time to remit, score on the Hamilton Anxiety scale, and a patient rated depression scale (QIDS).
Lurasidone is also approved for schizophrenia at higher doses (up to 160mg/day). At least twice as much of the drug is absorbed when food is in the stomach, so it is recommended that patients take it one to two hours after dinner or after a snack of 350 calories or more. The drug has an excellent side effects profile, as it is weight- and metabolically- neutral (i.e. it does not increase blood glucose, cholesterol, or triglycerides).
The atypical antipsychotic quetiapine has been FDA-approved for bipolar depression for a number of years. It consistently performs better than placebo in bipolar depression, and unlike lurasidone, quetiapine is also FDA-approved for mania, as well as for long-term prevention of both manic and depressive episodes as an adjunct to either lithium or valproate. Quetiapine is also superior to placebo for prevention of both manic and depressive episodes as a monotherapy, but is not FDA-approved for this indication. A good target dose for bipolar depression is 300mg/day of the extended release preparation taken several hours prior to bed time. Higher doses of 400 to 800mg/night are used for mania and schizophrenia. Quetiapine is also FDA-approved as an adjunct to antidepressants in unipolar depression. The drug has sedative side effects, perhaps because of its potent antihistamine effects. It can also increase weight, glucose, and cholesterol slightly more than placebo.
Olanzapine and Fluoxetine
Olanzapine (Zyprexa) and a combined preparation of olanzapine and fluoxetine (Symbyax) are also approved for bipolar depression, but many guidelines suggest that these be considered secondary treatments because they are associated with weight gain and adverse metabolic effects.
Cariprazine Effective in Bipolar Depression and Mania
At the 2014 meeting of the International College of Neuropsychopharmacology, researcher Suresh Durgam presented a poster on the first study of the atypical antipsychotic cariprazine in bipolar depression. There have also been three positive placebo-controlled studies of the drug in mania. It is a dopamine D2 and D3 partial agonist, with greater potency at the D3 receptor than the atypical antipsychotic aripiprazole (Abilify). In the large placebo-controlled eight-week study, doses of 1.5mg/day were superior to placebo, but higher (3mg) and lower doses (0.75mg) were not.
Another poster presented by the same research group also reported that augmentation of antidepressants with cariprazine in unipolar depression had results that were significantly better than placebo.
Editor’s Note: While all atypical antipsychotics that have been tested for mania have antimanic efficacy (lurasidone has not been studied in mania), their antidepressant profiles differ considerably. Only the three atypical antipsychotics noted above (olanzapine/fluoxetine, quetiapine, and lurasidone) are FDA-approved for bipolar depression, and in light of recent findings, cariprazine is likely to follow soon.
The atypical antipsychotics NOT approved for bipolar depression include: aripiprazole (Abilify), risperidone (Risperidol), and ziprasidone (Geodon), with the first atypical antipsychotic clozapine and the most recent ones not yet formally tested as far as this editor is aware, including asenapine (Saphris), iloperidone (Fanapt), and paliperidone (Invega).
Only the atypical antipsychotics aripiprazole and quetiapine are FDA-approved as adjunctive treatments to antidepressants in unipolar depression, and cariprazine may soon be added to this list.
Joanna Soczynska in Roger McIntyre’s lab at the University of Toronto presented a poster at the 2014 meeting of the International College of Neuropsychopharmacology (CINP) on the anti-inflammatory and neuroprotective antibiotic minocycline.
Twenty-seven patients with a major depression received minocycline in addition to the medications they were already being prescribed. Dosage was 100mg twice a day. Treatment with adjunctive minocycline was associated with significant improvement on several scales that measure depression severity.
Editor’s Note: What was particularly interesting was that a subset of patients achieved complete remission, raising the question whether these patients might have markers of inflammation that would predict this excellent response. The authors concluded that the “results provide a rationale for testing minocycline’s efficacy in a larger randomized, placebo-controlled trial.”
Exactly this type of study was proposed a year ago by researcher Andy Nierenberg and given the best marks by a National Institute of Mental Health review committee but was turned down for funding because the National Institute of Mental Health has implemented a new initiative, Research Domain Criteria (RDoC), that lays out new criteria for research, limiting funding to those studies that focus on a molecular target that spans several diagnoses.)
Methylene blue is a chemical compound that has been used to treat a variety of medical conditions. This drug has some actions that resemble lithium’s: it inhibits guanylate cyclase, which generates second messenger cyclic GMP, and decreases nitric oxide. New evidence shows it may help depression and anxiety in bipolar disorder when added to lamotrigine.
In patients with bipolar disorder who were all treated with lamotrigine, an active 65mg dose of methylene blue three times per day (for a daily total of 195mg) versus 15mg/day (an inactive dose that produces the same side effect of blue urine) was more effective at treating depression and anxiety in a 12-week crossover study. Side effects, in addition to blue urine, included infrequent nausea, diarrhea, headache, and a burning sensation in the urinary tract. Of the 37 randomized study participants, 27 completed both phases of the entire six-month study. Martin Alda, a researcher who presented the double-blind randomized crossover data at the 2014 meeting of the International Society for Bipolar Disorders, indicated that he has also used this preparation clinically with success, although the pharmacy staff who prepared the capsules were not too happy, because everything the drug touches turns blue.
At the US Psychiatric Congress in 2013, researcher T. Ketter reported on two recent studies of armodafinal (Neuvigil), which is approved for the treatment of narcolepsy. Doses of 150mg/day did not perform significantly better than placebo in the treatment of bipolar depression (in contrast to an earlier positive study).
Editor’s Note: It appears that this drug will not play a major role in the treatment of bipolar depression, as some had hoped.