Our articles often focus on treatments that work, but it’s worth pausing to review the recent disappointments. They include an industry-sponsored trial of cariprazine (Vraylar) in major depression, a condition for which it has FDA approval as an augmentation to antidepressants.

Cariprazine

Cariprazine (Vraylar) is FDA approved for augmentation of antidepressants in major depressive disorder, but a new study casts doubt on its efficacy there. This industry-sponsored trial randomized 750 patients to receive cariprazine 1.5 mg, cariprazine 3 mg, or placebo as augmentation to their antidepressant. After six weeks, cariprazine failed to separate from placebo, although nonsignificant trends were seen in the higher 3 mg dose. The authors blamed the failure on a high placebo response rate, but equal responsibility falls on the drug itself, which yielded only a small effect size (0.3) in previous trials (Riesenberg R et al, J Clin Psychiatry 2023;84(5):22m14643).

Cariprazine is also FDA approved in bipolar depression, and its track record is uneven there as well. It failed in unpublished trials of bipolar II depression and had only a small effect in bipolar I depression. In contrast, both lumateperone and quetiapine proved effective in bipolar I and II depression.

Esketamine

Esketamine (Spravato) also posted a recent failure in a disorder where it is FDA approved: treatment-resistant depression. Esketamine showed early promise in this industry-sponsored trial of 252 patients, separating from placebo within 24 hours. Those benefits quickly subsided, however, and were no longer detectable by week four. This pattern is not out of character for esketamine. In its positive trials, it brought about rapid improvements that lessened over the first four weeks. Like cariprazine, its overall effect size in major depression is small (0.3) (Chen X et al, Neuropsychiatr Dis Treat 2023;19:693–707).

Zuranolone

Zuranolone is a GABAergic steroid that has been newly approved as Zurzuvae in postpartum depression. Its trials were consistently positive in that disorder, but it missed the mark in major depressive disorder. Like esketamine, zuranolone brought rapid improvement in major depression, but its benefits fizzled out within one to two weeks in several large trials. This is not surprising for a medication that resembles a benzodiazepine in both its mechanism and its rewarding qualities (see the January 2024 issue of The Carlat Psychiatry Report for reference).

Minocycline, simvastatin, and ­pimavanserin

The antibiotic minocycline, the statin simvastatin, and the novel antipsychotic pimavanserin (Nuplazid) brought unique mechanisms to depression. Although earlier, small studies were positive, each failed this year in well-designed randomized trials. Their failure on the larger stage may end these pursuits, although minocycline still has hope (Hellmann-Regen J et al, JAMA Netw Open 2022;5(9):e2230367; Husain MI et al, JAMA Netw Open 2023;6(2):e230147; Dirks B et al, Psychopharmacol Bull 2022;52(4):8–30).

Minocycline has enough positive trials in major depression to gain an endorsement from a 2023 meta-analysis (Qiu Y et al, Front Psychiatry 2023;14:1139273). Its mechanism is complex, involving neuroprotective, anti-inflammatory, glutamatergic, and monoaminergic activities. In one study, it worked preferentially in depressed patients with high levels of inflammation (as measured by a high-sensitivity CRP ≥3). The typical dose is 200 mg daily.

N-acetylcysteine (NAC)

NAC is the main antioxidant in the brain. It has been tested in various conditions over the past 20 years, but it has never had a straight record of success. Encouraging results in trichotillomania, depression, OCD, negative symptoms of schizophrenia, and cannabis use disorder have all been countered by negative studies of a similar size and design. At best, NAC works in bipolar but not unipolar depression, and it has a slow build. In the positive bipolar trial at a dose of 2,000 mg/day, it took four to six months to see an effect (Berk M et al, Biol Psychiatry 2008;64:468–475).

NAC may have a role in psychiatric symptoms that occur during a substance use disorder. Recently, it improved depression and anxiety in a small, placebo-controlled trial of opioid use disorder (Padoei F et al, Brain Behav 2023;13(1):e2823). Although it failed in a recent trial, it did work in an earlier PTSD trial that enrolled patients with comorbid addictions (Kanaan RA et al, Psychiatry Res 2023;327:115398).

On the other hand, NAC’s ability to directly reduce substance use looks less promising. Earlier, it failed in cocaine use disorder, and this year it failed in two small randomized controlled trials of alcohol use disorder (Morley KC et al, Alcohol Alcohol 2023;agad044; Kirkland AE et al, Neuropsychopharmacology 2023;48(8):1184–1193).

The MIND diet

The MIND diet, a Mediterranean-style approach to prevent dementia, gained popularity quickly when it was developed in 2015. It had robust support from basic science and epidemiologic studies, and a panel of US News–appointed experts ranked it the second best diet for overall health.

The MIND diet failed this year in its first randomized trial, a well-designed, three-year study that looked at cognitive outcomes on the diet compared to a control diet in 604 people. The participants entered the study with normal cognition but had characteristics that would predict a good response to the diet. They were older (average age 70), were overweight, ate a poor diet, and had a family history of dementia. Yet they had no benefit on objective measures of cognition or brain MRIs (Barnes LL et al, N Engl J Med 2023;389(7):602–611).

Those who purchased one of the two dozen MIND diet cookbooks can still find use for this approach. A similar diet treated major depressive disorder with a large effect size in three controlled trials, and improved childhood ADHD in another (see the November/December 2021 and October/November 2022 issues of The Carlat Psychiatry Report). Like the MIND diet, the nutritional plans in these studies were based on the heart-healthy Mediterranean and DASH diets. The difference? The MIND diet sets a stricter limit on cheese, based on a theory that diacetyl from cheese contributes to the amyloid plaques that are implicated in dementia.

CARLAT VERDICT 

It’s just as important to pay attention to negative results as to positive results. For the medications I’ve discussed in this article, we now believe the following:

• On average, we can expect weak effects from cariprazine in depression. 
• Esketamine’s antidepressant benefits decline after a few weeks. 
• Zuranolone is effective for postpartum depression but not for standard major depression. 
• Simvastatin and pimavanserin appear ineffective in depression.                            
• The picture is not yet clear for NAC and minocycline, which may have a role in certain types of depression.