Lithium Corrects Circadian Rhythm Abnormalities in Bipolar Depression
At a recent scientific meeting, researcher Monica Federoff described new findings about lithium’s effects in people with bipolar I disorder, especially regarding circadian rhythms. The 12-week study included 386 participants with bipolar I. Some participants responded well to lithium, but even those whose bipolar disorder did not remit saw improvements in total symptoms, depressive symptoms, and manic symptoms.
Only those who were classified as good responders to lithium treatment showed improvement in circadian symptoms. Their depression improved in the direction of more “morningness,” and the authors suggested that “stabilization of circadian symptoms of depression may be an essential feature of lithium’s therapeutic effects in [bipolar] I patients.”
Lumateperone Improves Bipolar Depression Symptoms
At a recent scientific meeting, Suresh Durgam of Intra-Cellular Therapies, Inc. reported on a study of lumateperone tosylate for the treatment of bipolar depression. Lumateperone tosylate is a mechanistically novel antipsychotic that has been approved by the US Food and Drug Administration for the treatment of schizophrenia.
In a double-blind, placebo-controlled study, the drug showed efficacy in bipolar I and II depression. In a 6-week study, 377 patients received either 42 mg/day of lumateperone or placebo, and 333 (87.4%) completed treatment. Lumateperone treatment significantly improved total scores on the Montgomery Asberg Depression Rating Scale (MADRS) compared with placebo. Item analysis revealed that 8 of 10 MADRS items improved significantly in comparison with placebo by day 29, and all items did by day 43. The largest effects were in reported sadness, apparent sadness, inner tension and reduced sleep. Durgam and colleagues concluded that lumateperone at a dose of 42mg improves a broad range of symptoms in bipolar I and bipolar II depression.
Sunovion Drug in Development Targets 5HT7 and D2 Receptors to Treat Bipolar Depression
At a recent meeting, President and CEO of Sunovion Pharmaceuticals Antony Loebel presented the results of a recent double-blind, placebo controlled study of a drug in development for the treatment of bipolar depression, currently known as SEP-4199. The drug has a fixed ratio of 85% aramisulpride and 15% esamisulpride that target serotonin 5-HT7 receptors and dopamine D2 receptors, respectively. The drug was optimized to amplify the antidepressant effects that come from affecting 5-HT7 while minimizing D2-related side effects.
A total of 344 patients were randomized into three equal groups, in which patients received placebo or a fixed dose of SEP-4199, either 200mg/day or 400mg/day.
The results were promising. After 6 weeks, scores on the Montgomery Asberg Depression Rating Scale (MADRS) were higher among patients who received SEP-4199. The results were very close to statistical significance (p=0.054), with the placebo group showing a large improvement that may have contributed to the lack of difference across groups. In each dosage group, there was greater improvement in MADRS scores than was seen in the placebo group. There was also greater improvement on the Quick Inventory of Depression Symptomatology (QIDS-SR-16) and on the Hamilton Anxiety Rating Scale (HAM-A) in each dosage group compared to placebo.
Loebel concluded that the results showed proof of concept for the use of SEP-4199 to treat bipolar depression, and they plan to continue their research on the drug.
Lurasidone Effective Long-Term in Pediatric Bipolar Depression
At the 2020 meeting of the American Society of Clinical Psychopharmacology, researcher Manpreet Singh presented data showing that children aged 10–17 with bipolar depression had an excellent long-term response to the antipsychotic medication lurasidone (trade name Latuda).
Lurasidone has been approved by the US Food and Drug Administration as a monotherapy treatment of bipolar depression in children and adolescents since 2018. Following a six-week double-blind study comparing lurasidone with placebo in 305 children and adolescents, Singh and colleagues carried out an open-label extension study in which all of the young participants, including those in the placebo group, had the option of taking lurasidone for up to two more years.
Of those, 195 children completed one year of treatment, and 93 completed two years of treatment. Rates of response were 51.0% after the six-week preliminary study; 88.4% at one year; and 91.1% at two years. Rates of remission were 24.3% after the six-week study; 61.3% at one year, and 75.6% at two years, while rates of recovery were 17.7% after the preliminary study; 53.8% at one year; and 73.8% at two years.
This improvement in depression had a strong correlation with improvement in functioning, as measured by the Children’s Global Assessment score (CGAS). The results show progressive increases in rates of response, remission, and recovery with duration of treatment that are associated with improvement in functioning.
In Phase 3 Clinical Trials, Antipsychotic Treatment Lumateperone Is Found Effective in Bipolar Depression
Lumateperone is an antipsychotic medication that is currently approved by the US Food and Drug Administration for the treatment of schizophrenia (under the trade name Caplyta). New studies suggest that the drug is also effective in bipolar I and bipolar II depression.
Lumateperone modulates the activity of the neurotransmitters dopamine, serotonin, and glutamate. It modulates D1 and D2 dopamine receptors, partially activating presynaptic receptors while partially blocking postsynaptic receptors. Lumateperone acts as an antagonist blocking serotonin 5-HT2A receptors, and it augments activity at both NMDA and AMPA glutamate receptors.
Because of lumateperone’s complex pharmacology, it is not clear which of these activities are primarily responsible for its antidepressant and antipsychotic activities.
New research presented at the 2020 meeting of the International Society for Bipolar Disorders showed that lumateperone reduces bipolar depression.
Researcher Susan Kozauer presented research from a six-week study of 377 patients who were randomized to receive treatment with either 42mg of lumateperone (n=188), taken once daily in the evening, or placebo (n=189). The patients had been diagnosed with bipolar I or II disorder and were experiencing an episode of major depression.
Patients taking lumateperone saw significantly greater improvement in depression than those in the placebo group. Among those taking lumateperone, 60% of those who were markedly ill or worse at baseline improved to mildly ill or better, compared to 43% of those taking placebo.
Researcher Suresh Durgam described improvements in specific symptoms that make up the Montgomery-Åsberg Depression Rating Scale (MADRS) in those patients who received lumateperone. The greatest improvements compared to placebo were in sadness, inner tension, and reduced sleep. By the 29th day of the study, 8 of 10 items on the scale had improved significantly compared to placebo, and all items had improved by day 43.
The side-effects profile of lumateperone was presented by researcher Lakshmi Yatham.
Among those taking lumateperone, 8.5% experienced sleepiness compared to 1.1% of those in the placebo group, while 6.4% of the lumateperone group experienced nausea compared to 2.1% of the placebo group. Most effects were mild or moderate in severity. Changes in weight, metabolic measures, extrapyramidal motor effects, and prolactin were minimal in both the lumateperone group and the placebo group.
Editor’s Note: Lumateperone (Caplyta) joins a list of other atypicals that are efficacious in bipolar depression. These include olanzapine-fluoxetine (Symbyax), quetiapine (Seroquel), lurasidone (Latuda), and cariprazine (Vraylar). Lumateperone is currently only FDA-approved for schizophrenia, but approval for bipolar depression should be rapidly forthcoming based on the data presented at the ISBD meeting.
Bipolar depression used to be an orphan diagnosis, with few efficacious treatments. This is now beginning to change, and treating patients with bipolar disorder using antidepressants designed to treat unipolar depression (for which there is little evidence of efficacy) should begin to recede.
Improvement in Bipolar Depression on Open-Label Lurasidone
Researcher Katherine Burdick and colleagues of Brigham and Women’s Faulkner Hospital and Harvard University reported in a poster at the 2019 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) that youth between the ages of 10 and 17 with bipolar depression who continued taking lurasidone on a non-blind basis following a double-blind placebo-controlled six-week trial of the drug, or those who began taking lurasidone (for those who had been in the placebo group during the trial) saw improvement over a period of one to two years. All of the patients began the extension portion of the study at a dose of 20 mg/day.
Lurasidone appeared to be effective and well-tolerated. In addition, Burdick and colleagues reported a lack of cognitive difficulties in the youth taking lurasidone. Interestingly, a measure of visual learning substantially and progressively improved over the course of the study.
Treating Bipolar Depression in an Adolescent
At the 2019 meeting of the International Society for Bipolar Disorders, researcher Ben Goldstein discussed a case of a 15-year-old with bipolar depression and his recommended treatments for the adolescent. Goldstein endorsed the use of an atypical antipsychotic such as lurasidone, and perhaps also quetiapine. Goldstein noted 2015 findings from researcher Robert Findling that lamotrigine was significantly more effective than placebo in adolescents 13–18 years old, but was not effective in those aged 10–12.
(In adults, researcher John Geddes and colleagues found that in patients with an inadequate antidepressant response to quetiapine, the addition of lamotrigine was more effective than adding a placebo, both acutely and in long-term follow-up. The only caveat was that lamotrigine was less effective in those who were also being treated with folate.)
Editor’s Note: Some other treatments could augment the effects of the regimen proposed by Goldstein, including lithium and the antioxidant N-acetylcysteine, which, it should be noted, takes more than eight weeks to become effective. Vitamin D3 could also be considered, as it is often low in children with psychiatric disorders. One treatment that went unmentioned at the meeting was repeated transcranial magnetic stimulation, or rTMS, which is effective and well-tolerated in adolescents with depression.
For patients with more rapidly cycling bipolar disorder and only partial response to medications, the combination of the ‘three Ls’ (lurasidone, lamotrigine, and lithium) could have considerable appeal, given that each drug is from a different class of medications, has a different mechanism of action, targets a different mood phase, and is relatively well-tolerated both alone and in combination with other drugs.
Antioxidant Supplement Coenzyme Q10 Looks Promising for Bipolar Depression
Coenzyme Q10 (CoQ10) is an antioxidant that occurs naturally in the human body, but its levels decline with age, medical illness, and depression. In a randomized, controlled trial that was published in the Journal of Clinical Psychopharmacology in 2018, researcher Maryam Mehrpooya and colleagues found that adding coenzyme Q10 supplements to a treatment regimen improved bipolar depression compared to adding placebo.
The pathophysiology of bipolar disorder involves mitochondrial dysfunction, oxidative stress, and inflammation, and coenzyme Q10 can affect all of these pathways. It is also neuroprotective, and may help prevent the degeneration of neurons in people with Alzheimer’s, Parkinson’s, or Huntington’s diseases.
The study included a final total of 69 participants who were randomly assigned to receive either 200 mg/day of coenzyme Q10 supplements or placebo in addition to their normal treatment regimen, which had been stable for at least two months at the time of the study. Participants’ bipolar depression was rated at the beginning of the study, after four weeks, and after eight weeks. At the eight-week mark, coenzyme Q10 showed a statistically significant benefit over placebo with a large effect size. Three participants who received coenzyme Q10 experienced full remission of their depression, and 72% of those in the coenzyme Q10 group improved compared to only 12% of those who received placebo.
The study had some limitations. It was small, and twenty participants dropped out of the study before its completion, which may have inflated the findings.
Previous research found that coenzyme Q10 had benefits in specific populations. In two non-blind studies (studies in which participants know that they are receiving the treatment in question rather than possibly a placebo), 29 older patients with bipolar disorder improved when taking 800 mg to 1200 mg/day of coenzyme Q10. A randomized, controlled trial of coenzyme Q10 in people with multiple sclerosis and depression found that 500 mg/day reduced fatigue symptoms and depression. Coenzyme Q10 has also improved well-being and energy in small, controlled trials in people with breast cancer, Gulf War veterans, and elderly populations.
Taking coenzyme Q10 is low-risk. It had no adverse effects in the study by Mehrpooya and colleagues. Gastrointestinal reactions are possible, but can be managed by taking coenzyme Q10 with food and spreading out dosing throughout the day. Insomnia is also possible, but is less likely when coenzyme Q10 is taken early in the day. One effect to note is that coenzyme Q10 can interact badly with the blood-thinner warfarin.
Editor’s Note: The study by Mehrpooya and colleagues is interesting. Another antioxidant, N-acetylcysteine (NAC), also took 2 months to work in trichotillomania and bipolar depression, so patients should be warned not to expect a quick response with either coenzyme Q10 or NAC. Other potentially useful supplements include: Vitamin D3 (1500–5000 IU/day), folate or L-methylfolate, and acetyl-L-carnitine. Acetyl-L-carnitine may work more quickly, based on its presumed mechanism (increasing the production of the inhibitory metabotrophic glutamate receptor mGluR-2, which inhibits glutamate release).
High Baseline Levels Of C-Reactive Protein Predict Better Response To Lurasidone in Bipolar Depression
In a study presented at the 2017 meeting of the International Society for Affective Disorders, Charlies L. Raison and colleagues examined whether baseline levels of the inflammatory marker C-reactive protein (CRP) affected antidepressant response to the antipsychotic drug lurasidone in bipolar depression. The participants were divided into three double-blind groups: one received 20–60mg/day of lurasidone, another received 80–120 mg/day of lurasidone, and the third received placebo over a period of six weeks. The effect was dramatic—in people with CRP levels above 5 mg/L at the beginning of the study, lurasidone (at either dosage level) had a very large effect size (d=0.85), while in people with baseline CRP levels below 5 mg/L the effect size was smaller (d=0.35).
Interestingly, 118 of the participants (24.5%) had CRP levels above 5mg/L at baseline, indicating a substantial amount of inflammation was present in a quarter of the bipolar depressed patients. Higher levels of CRP at baseline were correlated with better improvement on specific items on the Montgomery–Åsberg Depression Rating Scale (MADRS): “lassitude” (or lack of energy), “apparent sadness,” “reported sadness,” and “pessimistic thoughts.” Raison and colleagues concluded: “These findings suggest that the efficacy of lurasidone in patients with bipolar depression may in part be linked to the inflammatory status of patients prior to treatment. If confirmed in prospective investigations, [the results of a wide-range CRP assay] may prove useful as a predictive biomarker that could help optimize the use of lurasidone for the treatment of patients with bipolar depression.”
Editor’s Note: In many instances, high levels of CRP predict a poor response to treatment (such as to selective serotonin reuptake inhibitor antidepressants (SSRIs) in unipolar depression), so these findings are of considerable interest. They also suggest the untested possibility that lurasidone has anti-inflammatory effects, as those with high levels of inflammation at baseline often respond better to drugs with direct anti-inflammatory effects such as celecoxib (Celebrex) or the antioxidant N-acetylcysteine (NAC).
Third Study Suggests Cariprazine Is Effective in Bipolar Depression
The atypical antipsychotic drug cariprazine (sold under the name Vraylar in the US) is currently approved by the US Food and Drug Administration for the treatment of schizophrenia and manic or mixed episodes of bipolar disorder. Based on recent successful phase 3 trials in bipolar depression, the pharmaceutical companies that produce cariprazine, Allergan and Gedeon Richter, plan to apply for a change in FDA labeling later this year to reflect the drug’s apparent ability to treat bipolar depression as well.
While many drugs can prevent or treat mania, treating bipolar depression has typically been more of a challenge. The most recent 6-week trial of cariprazine in 493 patients showed that a dose 1.5mg/day was significantly more effective than placebo at reducing depression ratings. (A dose of 3mg/day did not show superiority over placebo as it had in previous trials of cariprazine.)
Side effects reported in the trial were mild and included restless legs, nausea, and fatigue. Five percent of those who received cariprazine discontinued the drug due to side effects, compared to three percent of those who received placebo.
The mechanism by which cariprazine improves depression is not yet clear. The drug is a dopamine partial agonist, but unlike aripiprazole (Abilify) and brexpiprazole (Rexulti), which have more potent effects on D2 receptors than on D3 receptors, cariprazine is more potent at dopamine D3 receptors. Whether this difference accounts for the positive effects in bipolar depression that aripiprazole and brexpiprazole do not have remains to be seen.
