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Can we treat depression by targeting inflammation? Do SSRIs for post-stroke depression increase the risk of second intracranial hemorrhage? And how effective is the new combination treatment, olanzapine/samidorphan, for mitigating antipsychotic-induced weight gain? We will answer these questions in this Hospital Psychiatry Research Update Extravaganza!

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Published On: 03/10/2022

Duration: 9 minutes, 58 seconds

Related Articles: “Can We Treat Depression by Targeting Inflammation?,” The Carlat Hospital Psychiatry Report, October/November/December 2021

“New Combination Treatment Mitigates Antipsychotic-Induced Weight Gain,” The Carlat Hospital Psychiatry Report, July/August/September 2021

“SSRIs and Intracerebral Hemorrhage Risk,” The Carlat Hospital Psychiatry Report, April/May/June 2021

Victoria Hendrick, MD, has disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

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Transcript:

Dr Hendrick: Can we treat depression by targeting inflammation? Do SSRIs for post-stroke depression increase the risk of second intracranial hemorrhage? And how effective is the new combination treatment, olanzapine/samidorphan, for mitigating antipsychotic-induced weight gain?

Welcome to The Carlat Psychiatry Podcast. This is another episode from the The Caralt Hospital Psychiatry team. 

I’m Dr. Victoria Hendrick, the Editor-in-Chief of The Carlat Hospital Psychiatry Report, and a clinical professor at the David Geffen School of Medicine at UCLA. I’m also the director of inpatient psychiatry at Olive View — UCLA Medical Center.

Data from a new study by Dr. Zazula and colleagues suggests that inflammation may play a role in depression, prompting research into the efficacy of minocycline—a tetracycline antibiotic with anti-inflammatory effects—as an augmentation agent in the treatment of major depressive disorder. 

This study was a pooled data analysis from two multisite, double-blinded, placebo-controlled trials of minocycline 200 mg/day taken over 12 weeks. Participants were healthy adults who had a diagnosis of non-treatment-resistant, moderate-to-severe MDD and had already been receiving treatment for depression for the prior 2–6 weeks. Treatments included antidepressants (86%–89%), antipsychotics (29%–30%), and benzodiazepines (36%–40%).

Patients (n = 112) who were randomized to adjunctive minocycline (n = 57) were twice as likely as those on placebo (n = 55) to show a response to treatment, defined as a reduction in the Hamilton Rating Scale for Depression (HAM-D) score > 50%. They were also twice as likely to experience remission, defined as a HAM-D score < 7. Specifically, 57% of the minocycline group showed a response to treatment and 32% achieved remission. In comparison, 23% of the placebo group responded to treatment and 11% experienced remission.

Rates of adverse effects were comparable in the minocycline and placebo groups. Interestingly, the best responders were participants who used pain medications, had a longer duration of illness, and were older.

Minocycline is affordable, readily available, and has a low likelihood of producing antibiotic resistance (Husain MI et al, J Psychopharmacol 2017;31(9):1166–1175). Be cautious when prescribing to women of reproductive age: Minocycline reduces the efficacy of hormonal contraceptives and should not be used during pregnancy (category D).

Depression after strokes is very common, affecting about 50% of stroke patients. Many such patients are treated with SSRIs, which are generally effective but potentially dangerous because they can increase the risk of bleeding due to impaired platelet aggregation. This is especially dangerous in intracerebral hemorrhages (ICHs), which cause half of stroke mortality even though they represent only 10–15% of strokes. A recent study examined the safety of SSRIs in patients who recently had an ICH.

In a 2021 longitudinal study, researchers recruited a total of 1,279 patients who were treated for ICH at a single academic hospital from January 2006 to December 2017. Of these patients, 766 were diagnosed with depression and 281 were started on SSRIs. Patients receiving SSRIs were divided into two categories: high or low risk for a recurrent stroke. High risk criteria included: 1) a prior history of any type of stroke; 2) presence of apolipoprotein E2/E4 gene variants; 3) Black or Hispanic race; and 4) lobar ICH, as opposed to deeper tissues such as the basal ganglia, brainstem, and cerebellum.

SSRI use was associated with higher ICH recurrence (hazard ratio [HR] 1.3). 6.1% of high-risk patients on SSRIs had a recurrent ICH vs only 3.8% of those not on SSRIs. In contrast, low-risk patients on SSRIs were not at greater risk for a recurrence than those not on SSRIs (2.9% vs 2.3%). On the positive side, SSRIs were effective at resolving post-stroke depression, with patients on the meds 1.5 times more likely to experience remission. Low doses of SSRIs (< 50% maximum recommended dose) were just as effective as high doses (> 50% maximum recommended dose) and were associated with a lower risk of ICH recurrence (HR 1.25 and 1.61 respectively).

We have finally added a treatment for antipsychotic-induced weight gain into our arsenal. Thanks to recent research showing that samidorphan, an opioid receptor antagonist, appears to significantly lessen weight gain associated with the use of olanzapine. The combination treatment, olanzapine/samidorphan, received FDA approval on June 1, 2021.

In a 24-week, double-blind trial, 352 adults with schizophrenia were randomized to receive either olanzapine alone (n = 176) or a combination tablet of olanzapine and samidorphan (n = 176). Olanzapine doses were 10 or 20 mg daily, and the samidorphan dose was 10 mg daily. Alkermes, the manufacturer of the combination drug, sponsored the study. Exclusion criteria were strict and included treatment-resistant schizophrenia, substance use disorders, any clinically significant medical illness (eg, diabetes or hypertension), obesity (BMI > 30), and recent use of opioids or opioid antagonists.

At the 24-week endpoint of the study, patients on olanzapine/samidorphan gained 4.2% of their body weight, significantly less than the 6.6% gained by those taking olanzapine alone. Other key outcomes favoring olanzapine/samidorphan included the proportion of subjects who gained more than 10% of their baseline body weight (18% in the combined treatment group vs 30% in the olanzapine-only group) and the mean change in baseline waist circumference (2.4 cm in the combined treatment group vs 4.5 cm in the olanzapine-only group). Metabolic changes were minimal for both groups. Dropout rates were primarily associated with adverse events, impacting 12% of the combined treatment group and 9.8% of the olanzapine-only group.

The most common adverse events were weight gain and increased appetite (more in the olanzapine-only group), and somnolence and dry mouth (more in the combined treatment group). The addition of samidorphan did not affect antipsychotic efficacy. About one-third of patients dropped out due to side effects, loss to follow-up, or unspecified reasons.

To recap, consider adding minocycline to your list of augmentation strategies for the treatment of major depression. It’s a safe and well-tolerated treatment that might be particularly effective for depressed patients with pain and longer duration of illness.

And, SSRIs are effective in treating post-ICH depression, but for patients at high risk for another stroke, the mood benefits may not be worth the higher risk of having another ICH. A good tip from this study is to keep SSRI dosing low to avoid heightening the risk for stroke ­recurrence.

Lastly, adding samidorphan to olanzapine appears to decrease weight gain, but the effect in the study was only moderate. To put these results in perspective, a patient starting the trial at 150 pounds would have gained an average of 9.9 pounds on olanzapine vs 6.3 pounds on the combination. In addition, the exclusion criteria prevented many real-world patients from entering the trial. Especially in the inpatient world, it is unusual to find patients with schizophrenia who do not have either a substance use problem or a significant medical problem, so we don’t know if this study’s findings apply to our typical patients. Still, given how problematic AIWG can be for our patients, this new treatment may become a useful tool.

The print versions of these research updates are available for subscribers to read in The Carlat Hospital Psychiatry Report. 

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