From the Editor
Statins can help prevent MIs in people with high cholesterol. Can they also prevent psychiatric admissions for those with schizophrenia?
The question may seem odd, but there is evidence that statins can reduce symptoms in people with schizophrenia – though the evidence is light. That may not be as surprising as it seems: statins are anti-inflammatories, and a growing literature suggests neuro-inflammation is involved in major mental illness.
So should our patients receive medications like statins? The concept of repurposing common medications has gained attention.
This week, we look at a paper just published in JAMA Psychiatry. In their study, University College London’s Joseph F. Hayes and his co-authors consider the effect of statins, calcium channel blockers, and biguanides (such as metformin). Spoiler alert: they find that these medications reduce psychiatric hospital admissions and self-harm in people with serious mental illness.
In this Reading, we review the new paper about the not-so-new meds. We also take a quick look at another paper (on ketamine).
Repurposing and Psychiatric Illnesses
“Association of Hydroxylmethyl Glutaryl Coenzyme A Reductase Inhibitors, L-Type Calcium Channel Antagonists, and Biguanides With Rates of Psychiatric Hospitalization and Self-Harm in Individuals With Serious Mental Illness”
Joseph F. Hayes, Andreas Lundin, Susanne Wicks, Glyn Lewis, Ian C. K. Wong, David P. J. Osborn, Christina Dalman
JAMA Psychiatry, 9 January 2019 Online First
Serious mental illnesses (SMIs), including bipolar disorder (BPD), schizophrenia, and nonaffective psychoses (NAP), are associated with high levels of morbidity and are challenging to treat. Many drugs have been identified as having potential for repurposing in these disorders. We cross-referenced these drugs with the most commonly prescribed drugs in the general population. We chose to investigate the following 3 classes of drugs for which we might expect clinical benefit: hydroxylmethyl glutaryl coenzyme A reductase inhibitors (HMG-CoA RIs; ie, statins), L-type calcium channel (LTCC) antagonists (eg, verapamil hydrochloride), and biguanides (eg, metformin hydrochloride).
A recent meta-analysis of statins as adjunctive therapy for schizophrenia included 6 placebo-controlled randomized clinical trials (RCTs) and found a reduction in the Positive and Negative Symptom Scale scores in patients receiving statins for 12 weeks; however, only 169 received active treatment, and the reduction fell below the threshold considered clinically meaningful. Theorized mechanisms for HMG-CoA RI psychiatric action are via anti-inflammatory effects or via increased absorption and central nervous system uptake of antipsychotics. A systematic review and meta-analysis of LTCC antagonists for the treatment of BPD included 2 RCTs of verapamil vs placebo and 4 of verapamil vs lithium for the treatment of mania. The investigators found no evidence of an effect. However, no trials of other LTCC antagonists and no studies in BPD depression or prophylaxis have been performed. Evidence of calcium dysregulation in BPD has long been available; this evidence is supported by more recent pharmacologic, genetic, and molecular findings. Similarly, calcium signaling is implicated in the etiology of schizophrenia, where LTCC antagonists are also a potential adjuvant treatment. However, very limited and inconsistent trial evidence for their use in this disorder exists. A trial of metformin has been undertaken to counter antipsychotic-related weight gain, but metformin is also hypothesized to improve cognitive and mood dysfunction symptoms via mitigation of metabolic disturbances. Therefore, although none of these drugs have been comprehensively investigated as repurposed agents to improve mental disorders, each has a theoretical basis for effectiveness.
We investigated whether people in the Swedish population with SMI had lower rates of psychiatric hospitalization and self-harm during periods when they were prescribed HMG-CoA RIs, LTCC antagonists, and biguanides.
Here’s what they did:
- The authors did within-individual cohort studies, drawing data from several Swedish national databases, including the National Patient Register, and covering a period from 1973 to 2016, with a focus on people with schizophrenia, bipolar disorder, and non-affective psychosis.
- In terms of medications: “the main exposure was defined as treatment with HMG-CoA RIs, LTCC antagonists, or biguanides” using the Prescribed Drug Register. A medication period was defined as a sequence of at least 2 prescriptions within no more than 3 months between consecutive prescriptions.
- Outcomes considered: hospitalizations and self-harm.
- Different statistical analyses were done, including within-individual analyses using stratified Cox proportional hazards regression.
Here’s what they found:
- There were 76,759 patients with bipolar, 30,954 with schizophrenia, and 34,978 with non-affective psychosis for a total of 142,691 patients.
- In terms of HMG-CoA RIs: Reduced rates of psychiatric hospitalization in bipolar, schizophrenia, and NAP, and reduced self-harm rates in bipolar and schizophrenia (aHR: 0.86, 0.75, 0.80, 0.76, 0.58).
- In terms of LTCC antagonists: Reduced rates of psychiatric hospitalization and self-harm in subgroups with bipolar, schizophrenia, and NAP (0.92 and 0.81, 0.80 and 0.30, 0.89 and 0.56).
- In terms of biguanides: Reduced rates of psychiatric hospitalization and self-harm in subgroups with bipolar, schizophrenia, and NAP (0.92 and 0.81, 0.80 and 0.30, 0.89 and 0.56).
- This is an interesting study.
- To summarize: these common medications did help those with mental illness.
- It’s easy to see the attractiveness of these medications – they are collectively inexpensive and safe. As the authors conclude: “If substantiated, this study has considerable implications for clinical practice and drug development. The study drugs – HMG-CoA RIs, LTCC antagonists, and biguanides – are globally licensed, commonly used, cheap, and relatively safe medications. They are therefore ideal candidates for repurposing. Understanding their mode of action on the central nervous system may facilitate better understanding of the pathophysiology of SMI and offer opportunities for innovative pharmacotherapy development.”
- How much of the medications’ effects were due to cofounding factors? On Twitter, Hayes writes: “In this type of study is impossible to totally rule out that these associations reflect something other than a benefit of the drugs themselves. In particular, times when people were taking the drugs studied may be periods when they were receiving more support or were more well.”
- The paper also considered the use of thiazide diuretics – which aren’t known to have psychiatric implications. The authors write: “Thiazide diuretics, a group of medications that have no theorized basis for improving psychiatric symptoms, were not associated with rates of psychiatric hospitalization or self-harm rate but were associated with reduced rates of nonpsychiatric hospitalization. This finding suggests that medication adherence in and of itself is not a proxy for mental state stability, which would be reflected in reduced rates of psychiatric hospitalization and self-harm.”
- On Twitter, Hayes cautions that these current findings shouldn’t change treatment. He calls for more study (and, in particular, RCTs). You can find his tweets here: https://twitter.com/J_F_Hayes/status/1083032506268614656.
- Repurposing is an active area of research. A past Reading considered statins combined with SSRIs for depression. In The American Journal of Psychiatry paper, the authors found that statins reduced hospital contacts. The Reading can be found here: http://davidgratzer.com/reading-of-the-week/reading-of-the-week-battling-the-black-dog/.
- Let’s stick with the topic of new treatments but leave behind common medications. The British Journal of Psychiatry has just published paper on ketamine: “Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo-controlled, proof-of-concept study.” Involving 41 participants (mostly men), people with treatment-resistant depression were randomized to the intervention (oral ketamine, 1/mg kg, thrice weekly for 21 days) and placebo.
A quick word of caution: the n was 18 in the intervention group.
The full study is here: https://www.cambridge.org/core/journals/the-british-journal-of-psychiatry/article/repeated-oral-ketamine-for-outpatient-treatment-of-resistant-depression-randomised-doubleblind-placebocontrolled-proofofconcept-study/76898B0B3980372F9EE79043F55A08FD.
Ketamine has been considered in past Readings including a paper on inpatient care. See: http://davidgratzer.com/reading-of-the-week/reading-of-the-week-suicidal-get-a-postcard-the-new-jcp-paper-on-suicide-prevention-also-ketamine-inpatients/.
Reading of the Week. Every week I pick articles and papers from the world of Psychiatry.