Adjunctive Simvastatin in Early Schizophrenia

VitaliiVodolazskyi/AdobeStock

RESEARCH UPDATE

CASE VIGNETTE

“Ms T” is a 25-year-old African American female with an 8-year history of chronic schizophrenia. The onset of her illness was at age 17, and symptoms included auditory hallucinations of demonic figures, visual hallucinations of dead people, delusions of reference that the television is talking about her and thought broadcasting. She was stabilized on antipsychotic medication and has never required psychiatric hospitalization.

On routine metabolic monitoring at age 19, the patient was found to have elevated total (212 mg/dL) and LDL (160 mg/dL) cholesterol, low HDL cholesterol (37 mg/dL), and normal triglycerides (78 mg/dL). A decision was made to start her on adjunctive simvastatin. Subsequently, over the next year her lipid panel normalized except for persistent low HDL (37-40 mg/dL). However, there were no clinically appreciable changes in her symptoms or cognitive function during that time period.

Studying Simvastatin

Many patients with schizophrenia-spectrum disorders (SSDs) do not achieve illness remission using approved treatments.¹ Therefore, clinicians should explore novel therapeutic strategies. One potential mechanistic lead is immune dysregulation, given evidence for increased inflammation in schizophrenia.² Several previous studies have targeted inflammation in schizophrenia, with heterogeneous results.³ Statin drugs reduce cholesterol, metabolic syndrome, and cardiovascular mortality—which is prevalent in schizophrenia—and also cross the blood-brain barrier.⁴ Several small studies have shown potential benefits of adjunctive statins in SSDs.³ The Table outlines clinical trials of adjunctive statins in the treatment of schizophrenia.

Table. Clinical Trials of Adjunctive Statins in the Treatment of Schizophrenia

Sommer and colleagues⁵ performed a 12-month, double-blind, randomized placebo-controlled, multicenter trial of simvastatin 40 mg/day to patients with SSDs. Drawn from Dutch inpatient and outpatient settings between November 2013 and February 2019, eligible participants had a DSM-IV diagnosis of SSD (295.x or 298.9) within the past 3 years. Participants were randomized 1:1 to simvastatin or placebo, using block-randomization with stratification for study site and sex. Participants visited the research center 8 times over 2 years, and they were excluded if blood cholesterol was > 8 mmol/L at any visit. Raters were blinded to cholesterol results.

Primary outcomes were symptom severity as measured by the Positive and Negative Syndrome Scale (PANSS) and neurocognitive functioning as assessed by the Brief Assessment of Cognition in Schizophrenia (BACS) at the end of 12 months of treatment. Secondary outcomes included PANSS subscale scores, global assessment of functioning, extrapyramidal symptoms, akathisia, depressive symptoms, and the metabolic syndrome. Data were analyzed using linear mixed models for repeated measurements.

One hundred nineteen participants were randomized, and 90 completed 12 months of treatment. The follow-up 1 year after the end of treatment was completed by 70 participants. There was no main effect of simvastatin treatment on PANSS total score after 12 months. However, the treatment by time interaction effect was significant, indicating that group differences in symptom severity differed over time. The simvastatin group had significantly lower PANSS total scores at 6 months (mean difference -4.8 points) and 24 months (mean difference 4.7 points) post-baseline. There was no effect on simvastatin on cognitive performance (BACS composite and subtask scores) after 12 months.

There was a significant treatment by time interaction effect, with higher general functioning (GAF) in the simvastatin group at 24 months (mean 4.9 points). There was also a significant decrease in total cholesterol, LDL cholesterol, and non-HDL cholesterol in the simvastatin group over time compared to placebo. Serious adverse events were more common the placebo group (19% versus 7%). There were no significant differences in adverse events between participant groups, including those particularly relevant to treatment with statins, namely dark-colored urine and myalgias.

The authors concluded that, although well-tolerated, simvastatin augmentation is not an effective treatment for symptom severity or cognition early-phase SSDs. Treatment adherence, particularly given the long duration of the trial, may have contributed to negative findings and is a notable study limitation. Another possibility is that only a subset of patients—namely those who are enriched for inflammation—may show improvement in symptoms and cognition with treatment with simvastatin. The authors note that the early-phase SSD population may have been suboptimal, given that metabolic syndrome was (largely) absent in these patients.

The Bottom Line

Antiinflammatory augmentation may not be beneficial for symptom severity and cognition in schizophrenia, although this does not preclude the possibility that a subset of patients may benefit from this approach. Future studies—especially in patients with evidence of inflammation—are warranted.

Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times^TM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

References

1. Levi L, Bar Haim M, Burshtein S, et al. Duration of untreated psychosis and response to treatment: an analysis of response in the OPTiMiSE cohort. Eur Neuropsychopharmacol. 2020;32:131-135.

2. Çakici N, van Beveren NJM, Judge-Hundal G, et al. An update on the efficacy of anti-inflammatory agents for patients with schizophrenia: a meta-analysis. Psychol Med. 2019;49(14):2307-2319.

3. Miller BJ, Goldsmith DR. Evaluating the hypothesis that schizophrenia is an inflammatory disorder. Focus (Am Psychiatr Publ). 2020;18(4):391-401.

4. Castilla Guerra L, del Carmen Fernández Moreno M, López Chozas JM, Jiménez Hernández MD. Statins in stroke prevention: what an internist should know. Eur J Intern Med. 2008;19(1):8-14.

5. Sommer IE, Gangadin SS, de Witte LD, et al. Simvastatin augmentation for patients with early-phase schizophrenia-spectrum disorders: a double-blind, randomized placebo-controlled trial. Schizophr Bull. 2021:sbab010.

6. Chaudhry IB, Husain N, Drake R, et al. Add-on clinical effects of simvastatin and ondansetron in patients with schizophrenia stabilized on antipsychotic treatment: pilot study. Ther AdvPsychopharmacol. 2017;4(3):110–116.

7. Ghanizadeh A, Rezaee Z, Dehbozorgi S, et al. Lovastatin for the adjunctive treatment of schizophrenia: a preliminary randomized double-blind placebo-controlled trial. Psychiatry Res. 2014;219(3):431-435.

8. Sayya M, Boostani H, Ashrafpoori M, et al. Effects of atorvastatin on negative sign in chronic schizophrenia: a double blind clinical trial. Iran J Pharm Res. 2015;14(4):1269-1274.

9. Tajik-Esmaeeli S, Moazen-Zadeh E, Abbasi N, et al. Simvastatin adjunct therapy for negative symptoms of schizophrenia: a randomized double-blind placebo-controlled trial. Int Clin Psychopharmacol. 2017;32(2):87-94.

10. Vincenzi B, Stock S, Borba CP, et al. A randomized placebo-controlled pilot study of pravastatin as an adjunctive therapy in schizophrenia patients: effect on inflammation, psychopathology, cognition and lipid metabolism. Schizophr Res. 2014;159(2-3):395-403.