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Child Psychiatrist /Adult Psychiatrist

The Solution to a 'Common and Hazardous' Symptom of Bipolar Disorder?

Recent research highlights the potential role of an atypical antipsychotic to treat anxiety, a prevalent and undertreated symptom in bipolar I disorder (BPD). Notably, investigators said, the drug comes without the typical metabolic side effects, including weight gain, associated with this drug class.

A post hoc analysis of pooled data from two trials comparing two different doses of cariprazine (Vraylar) to placebo showed it was consistently effective not only in alleviating bipolar depression but also in improving symptoms of anxiety.

Symptom of Bipolar Disorder

"Since this was a post hoc analysis, one has to be careful about not overstating the findings," study investigator Roger McIntyre, MD, professor of psychiatry and pharmacology, University of Toronto, Toronto, Ontario, Canada, and head of the Mood Disorders Psychopharmacology Unit, told Medscape Medical News.

"But what we can say is that anxiety has been an under-researched, undertreated symptom dimension in BPD, and these findings about cariprazine are very promising," said McIntyre, chair and executive director of the Brain and Cognition Discovery Foundation, Toronto, Canada.

The analysis was published in International Clinical Psychopharmacology and was presented as a poster at the 2023 Neuroscience Education Institute, Colorado Springs, Colorado.

Ubiquitous, Common, Hazardous

Anxiety in BPD is "ubiquitous, common, and hazardous," McIntyre said. "We talk so much about depression and mania as cardinal presentations, but someone could make a case that in that trifecta, we're missing anxiety."

In patients with BPD and anxiety, "the index episode is much more difficult to treat, there's a longer time to remission, lower rates of recovery, and a shorter time to recurrence," noted McIntyre, chair of the board of the Depression and Bipolar Support Alliance.

Anxiety also may "represent a portent of other things that can add more to the trouble, like alcohol, illicit drugs, or cannabis use — especially now that cannabis is no longer illegal," McIntyre said.

Unfortunately, he said, "there hasn't been an organized, systematic approach to developing a therapy for anxiety in BPD." Rather, patients are prescribed benzodiazepines, gabapentinoids, or selective serotonin reuptake inhibitors, all of which have limitations, he added.

Some atypical antipsychotics such as quetiapine have been shown to be helpful with anxiety but "have a lot of baggage and side effects — especially sedation, somnolence, weight gain, and metabolic problems," McIntyre noted.

Cariprazine is a dopamine D3-preferring D3/D2 partial agonist, a serotonin 5-HT1A receptor partial agonist, and 5-HT2B receptor antagonist, which has shown anxiolytic-like activity in rodent models.

It was approved by the US Food and Drug Administration to treat mania, depression, and mixed episodes of BPD in 2015 and BPD in 2019.

McIntyre and his team believed there was an opportunity in the completed randomized controlled trials of cariprazine in BPD to conduct a post hoc analysis of its impact on anxiety.

'Cornerstone Mood Stabilizer'

The researchers pooled data from two phase 3, randomized, double-blind, placebo-controlled studies in adults with BPD experiencing a current major depressive episode.

The pooled intention-to-treat population consisted of 952 patients with BPD (mean age, ~43 years; 62% female) randomized to receive either 1.5 mg/d, 3 mg/d of cariprazine, or placebo. Patients were divided into two subsets: Lower or higher anxiety (defined as a Hamilton Anxiety Rating Scale [HAM-A] total score of < 18 and ≥ 18, respectively). Patients also completed the Montgomery-Åsberg Rating Scale (MADRS).

A third of the patients received a placebo, a third received the 1.5 mg/d dose, and a third received the 3 mg/d dose. Demographic and baseline characteristics were similar between the subsets.

Results showed there was a statistically significant change in HAM-A total score for cariprazine 1.5 mg/d (P = .0027). The investigators also found a statistically significant change in MADRS total score change for cariprazine 1.5 mg (P = .0200) in the higher anxiety subset. The rate of remission was significantly greater for cariprazine 1.5 mg/d in the higher and lower anxiety subsets (P = .0172 and P = .0004, respectively).

In addition, the change in HAM-A total score change was statistically significant for cariprazine 1.5 mg/d in the higher anxiety subgroup (P = .0105) and the 3 mg/d dose in the lower anxiety subgroup (P = .0441).

McIntyre hopes these findings can be replicated in other trials.

"Clinically, I find that many patients who take cariprazine don't require as many benzodiazepines or other medications for anxiety, and it's one of the better-tolerated medications without metabolic complications or weight gain, so it's become a cornerstone mood stabilizer," he said.

Polypharmacy Avoided

Another recent study retrospectively analyzed medical records of close to 40 adult patients with BPD I who were receiving treatment with aripiprazole for bipolar depression and then switched to cariprazine.

"We wanted to conduct a study in depressed patients who had gained weight on aripiprazole and then directly switched to cariprazine. It improved their mood and helped mitigate weight gain, thereby avoiding polypharmacy of additional antidepressants and weight loss agents," study investigator Maxwell Zachary Price, a medical student at Hackensack Meridian School of Medicine, Nutley, New Jersey, told Medscape Medical News.

"In our general outpatient psychiatry practice, we've treated many adult patients with oral aripiprazole for maintenance of BPD," the study's senior investigator, Richard Price, MD, clinical assistant professor of psychiatry at Weill Cornell Medical College, New York City, added.

Aripiprazole is associated with weight gain. Moreover, aripiprazole "hasn't shown efficacy in managing BPD," he said.

Most patients in Price's practice are insured through Medicaid, which mandates treatment with aripiprazole before covering cariprazine. "We noticed their weight had been creeping up over the years, and they also were experiencing depressive symptoms," he said.

The requirement to initiate treatment with aripiprazole before switching to cariprazine offered Price an opportunity to compare the two agents in this real-world setting by retrospectively reviewing the charts of 37 patients with BPD (23 females and 14 males who made the switch). The patients had been taking aripiprazole for a mean duration of 94.9 weeks and had experienced a mean increase in body weight of 16.1% ± 12.3% on aripiprazole before switching.

Patients who were taking 2 mg-10 mg of aripiprazole were switched to 1.5 mg of cariprazine, while those taking ≥ 15 mg of aripiprazole were switched to 3 mg of cariprazine.

"Patients tolerated the switch well and maintained stability during the transition," and "no patients discontinued cariprazine during the study," Price said.

After a mean duration of 36.7 weeks (range, 1-127 weeks), the patients showed a decrease in Clinical Global Impression-Bipolar Severity of Illness Scale score from a mean of 5.0 ± 0.9 to a mean of 2.8 ± 0.7 (t = −12.75, P < .00001).

The patients' weight dropped from a mean of 90.3± 21.5 kg on aripiprazole to a mean of 83.9 ± 19.2 kg on cariprazine (t = −4.22, P < .001).

Two patients experienced initial nausea that resolved by taking the medication with food, and two experienced initial restlessness that resolved with dosage reduction.

"We found that the patients were lighter in mood, body habitus and weight, and less agitated and their mental alertness and concentration improved as well," said Price. He hopes that further research in randomized blinded trials will corroborate the findings.

Hypothesis-Generating Research

Joseph Cerimele, MD, MPH, associate professor of psychiatry and behavioral sciences, University of Washington, Division of Population Health, UW Medicine, Seattle, Washington, said the research findings are "hypothesis-generating."

Ciremele, who wasn't involved with either study, said many clinicians and researchers are trying to tailor treatment options to match patient characteristics, and these studies and other similar research, "help us all ask questions related to concurrent symptoms in bipolar depression."

However, the post hoc analysis was a secondary analysis of an efficacy trial where individuals with concurrent anxiety disorders were excluded. "So, a next step might be to evaluate this and other treatments in individuals with BPD and concurrent anxiety disorders," he said.

The study by Jain et al was funded by AbbVie. McIntyre had received research grant support from CIHR/GACD/National Natural Science Foundation of China and the Milken Institute; speaker/consultation fees from Lundbeck, Janssen, Alkermes, Neumora Therapeutics Inc., Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome Therapeutics, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular Therapies, NewBridge Pharmaceuticals, Viatris, Abbvie, and Atai Life Sciences. McIntyre is the CEO of Braxia Scientific Corp. His coauthors' disclosures are listed in the original paper. Richard Price had received honoraria from AbbVie, Alkermes, Allergan, Intra-Cellular Therapies, Janssen, Jazz, Lundbeck, Neuronetics, Otsuka, and Supernus. Maxwell Price and Cerimele reported no relevant financial relationships.

Note: This article originally appeared on Medscape

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