Sedative-Hypnotics

Sleep problems are very common in schizophrenia and usually multifactorial, defying one simple solution such as prescribing a hypnotic agent. Often, a specific, diagnosable sleep disorder is present. Common disorders are obstructive sleep apnea [19, 20] or simply poor sleep hygiene and sleep-wake cycle disturbances [21] for which benzodiazepines are of little to no use. Patients with no day structure, who sleep in until noon, are inactive during the rest of the day, and perhaps even take a nap, will simply not be tired before midnight. In those patients, prescribing a hypnotic will exacerbate rather than help the problem. Some more activating antipsychotics (i.e., antipsychotics who are not sedating) can cause insomnia, and adding a benzodiazepine at night remedies this problem. Insomnia can be a problem for patients who are used to sedating antipsychotic when they are switched to less sedating antipsychotics. If I need to symptomatically treat insomnia, I will consider a sedative-hypnotic (e.g., zolpidem) and not forego this medication class at the expense of more risky approaches (e.g., the antipsychotic quetiapine which causes weight gain and increases QTc). The American Society of Sleep Medicine published guidelines with recommendations for and against specific agents [22]. Other than confirming the value of the Z-drugs, they recommend doxepin (3 mg or 6 mg) or suvorexant for sleep maintenance insomnia and ramelteon for sleep onset insomnia. They specifically recommend against using low-dose trazodone, melatonin, or diphenhydramine which are all commonly used medications in community settings because of their perceived safety despite little to no evidence for their efficacy.

Lamotrigine

Lamotrigine has shown some promise in controlled clinical trials as an add-on medication for patients with schizophrenia [25]. I try it in patients with persistent psychosis, particularly if they have chronic dysphoria or dysthymia as well (remember, it is FDA-approved for maintenance treatment of bipolar disorder but seems to be mostly used as a treatment for bipolar depression [26]). Clinical trials in schizophrenia have generally used total daily doses of 200 to 400 mg per day. I have found lamotrigine to be one of the better-tolerated antiepileptic drugs used in psychiatry, with little sedation or weight gain. However, you must strictly follow titration guidelines to minimize the risk for Stevens-Johnson syndrome or similar cutaneous reactions [27]. After a decade or so of using it, I admit that my enthusiasm has waned. Two more recent clinical trials have been disappointing in that they failed to replicate earlier positive trials [28]. I mostly reserve its use now for patients with refractory psychosis on clozapine but may still use it for patients with prominent depressive symptoms who do not want to try lithium or an antidepressant.

Valproate

Valproate may be one of the most overused medications in the management of schizophrenia spectrum disorders, despite lack of evidence for its benefit [29]. It is somewhat useful for the acute management of psychosis by hastening a response [30], although its role in the long-term management of schizophrenia is questionable. When valproate is combined with an antipsychotic, acutely psychotic patients become calmer more quickly than with the antipsychotic alone, as early as on the third day; however, both approaches lead to the same degree of improvement after several weeks of treatment [31]. I think it is a common mistake to simply continue valproate with an outpatient if it was added in the hospital for faster behavior control (which in and of itself is not a bad idea given the risks of injury if there is agitation and aggression during psychosis). For refractory and chronic irritability, valproate is frequently used (including by me), although the benefit of this approach is not well documented [29]. In one meta-analysis of antiepileptic drugs, valproate (and topiramate) was found to offer some benefit [32].

In my experience, valproate is not as well tolerated as many seem to think; sedation, worsened EPS, and weight gain are expectable problems (in addition to a host of potentially more severe problems such as pancreatitis). In women, take into account that valproate is associated with polycystic ovary syndrome (PCOS) and other endocrine abnormalities [33]. Worse, valproate is one of the most teratogenic agents psychiatrists prescribe, with well-documented risk for major congenital malformations [34]. Despite these risks, the adherence to guideline recommendations for valproate-treated female patients to prevent pregnancy (contraception) or poor pregnancy outcomes (folic acid supplementation) is low in patients with serious mental illness [35]. Taking into account these real-world difficulties in safely prescribing valproate, the best harm reduction approach may severely restrict the use of valproate in women of childbearing age (i.e., consider it contraindicated unless no other treatment exists). This stance was recently taken by the European Union’s FDA, the European Medicines Agency [36].

Carbamazepine and Oxcarbazepine

Apart from unclear efficacy for schizophrenia [37], the clinical use of carbamazepine is limited by enzyme induction and a host of potentially quite dangerous side effects (allergic skin reactions, aplastic anemia, and agranulocytosis). It should not be combined with clozapine because of its bone marrow toxicity. Carbamazepine is a pan-inducer of P450 enzymes which can make it difficult to reach sufficient antipsychotic drug levels. Stevens-Johnson syndrome and other toxic cutaneous reactions are well-established complications. Those are 10× more common in patients with a particular HLA genotype found in many Asian populations, and HLA genotyping is required before starting treatment in any patient who has Asian ancestry [38]. I consider carbamazepine a third-line add-on treatment unless there are electroencephalogram (EEG) abnormalities. Oxcarbazepine is sometimes used instead of carbamazepine as it has less, albeit not zero, enzyme induction [39]. Hyponatremia is a well-described long-term concern with both carbamazepine and oxcarbazepine, particularly in elderly patients, and more so for oxcarbazepine [40].

Topiramate

In one meta-analysis, topiramate was found to improve psychopathology globally while offering good tolerability when added to ongoing antipsychotic treatments [41]. In addition, patients lost weight. This is noteworthy as most medications used to treat schizophrenia are associated with weight gain. As noted earlier, topiramate was one of two antiepileptic drugs in a different meta-analysis of clozapine augmentation with antiepileptic drugs (the other drug being valproate) that offered some global benefit for clozapine-treated patients [32]. In this second analysis, topiramate had a high discontinuation rate due to side effects.

I have found topiramate quite effective for some weight loss in some patients. There may be a dose effect, and I use between 100 and 200 mg/day. (For comparison, topiramate is marketed for weight loss in a combination pill with phentermine, with the highest dose strength containing 92 mg of topiramate.) Like always in medicine, “results may vary,” as they say on TV. I once treated a patient who experienced a dramatic weight loss and who underwent an extensive cancer work-up until I discovered that his PCP had added topiramate for migraine prophylaxis. While tolerability of topiramate seems good in my patient population, I remain worried about possible negative effects on cognition. In patients with serious mental illness, somewhat worse cognition may neither be reported by patients nor easily observed by staff but still have functional consequences that go unrecognized. On the other hand, patients with normal cognition may be more sensitive to the cognitive side effects of topiramate, an effect observed in a study with normal volunteers [42].