Rajnish Mago, MD
Editor-in-Chief of Simple and Practical Mental Health and author of Side Effects of Psychiatric Medications: Prevention, Assessment, and ManagementDr. Mago has disclosed that he has no relevant financial or other interests in any commercial companies pertaining to this educational activity.
Editor’s note: In the June/July issue, Dr. Mago shared a sampling of his strategies for nausea, sweating, and dry mouth. We wrap up that conversation here with a few more tips on managing side effects.
TCPR: What’s your approach to antipsychotic-induced weight gain? Dr. Mago: Prevention is better than treatment. So, when possible, we should preferentially use medications that have a lower propensity for causing weight gain, like (alphabetically) aripiprazole (Abilify), brexpiprazole (Rexulti), lurasidone (Latuda), and ziprasidone (Geodon) (Musil R et al, Expert Opin Drug Saf 2015;14(1):73–96).
TCPR: And how do you manage weight gain when it happens? Dr. Mago: Of course, diet and exercise have to be part of the plan, but they aren’t easy for patients who are taking an antipsychotic medication because these medications can cause ravenous cravings for high-calorie foods. So, I’m not hesitant to also use a medication to treat the metabolic side effects. Any anti-obesity medicine can be used, but the one I prefer to start with is metformin. Many clinicians think that topiramate is the most effective medication for treating antipsychotic-induced weight gain, but this is not true. In a meta-analysis of studies on this topic, metformin was slightly more effective than topiramate (Maayan L et al, Neuropsychopharmacology 2010;35(7):15:20–30). And, compared to topiramate, metformin is much more benign. Topiramate often causes significant cognitive impairment and carries at least a 1% risk of renal stones. That may seem like a low number, but renal stones are a serious matter.
TCPR: Does metformin protect against metabolic syndrome or just against obesity? Dr. Mago: It does both. Metformin has multiple biological effects, but perhaps the most important one is in reducing insulin resistance, which is part of the metabolic syndrome. Lipid levels also tend to improve on metformin, but this may be an indirect effect from the weight loss.
TCPR: Why do you think metformin is not used more often? Dr. Mago: In my experience, there are two reasons for this. One is the belief that, since it’s an antidiabetic drug, it should only be used in people with elevated glucose. There is no truth in this. Patients with elevated blood sugar were actually excluded from the eight randomized controlled trials where metformin was studied for antipsychotic-induced weight gain. The other myth is that metformin will cause hypoglycemia and patients will have to check their glucose with a fingerstick at home. Fingerstick blood glucose monitoring is not necessary. Metformin does not increase the release of insulin and only partially reduces gluconeogenesis in the liver, so it is rare for hypoglycemia to occur (Kirpichnikov D et al, Ann Intern Med 2002;137(1):25–33).
TCPR: What are the risks with metformin? Dr. Mago: Metformin carries a black box warning that it can cause lactic acidosis. So we should not prescribe it to the elderly or to people who have a serious medical illness or who are at risk for hypoxemia. That would include systemic organ diseases like heart failure, respiratory failure, renal failure, and liver disease. If clinicians are unsure if a patient is at higher risk, they should consult with the primary care doctor.
TCPR: How do you dose metformin? Dr. Mago: I usually start with metformin XR 500 mg per day after the biggest meal of the day. After one week, if tolerated, I increase to 500 mg XR twice daily. After that, depending on tolerability, I generally try to go to 750 mg XR twice daily, and finally to 1000 mg XR twice daily. (Editor’s note: Many insurers do not cover the 1000 mg XR tablet but will cover two 500 mg XR tablets.) I usually start with the XR, but change to instant release if diarrhea is an issue.
TCPR: Do you check any labs with metformin? Dr. Mago: I’d check a comprehensive metabolic panel and pay attention to the creatinine and liver panel. I want to make sure that the serum creatinine is normal and the liver enzymes are normal or no more than a little bit elevated. It’s also good practice to check vitamin B12 at baseline and once a year, because metformin can deplete that vitamin.
TCPR: Do you give B12 with metformin? Dr. Mago: Most authors don’t recommend that. I’ll advise patients to take a multivitamin, which will give them some B12, but I don’t prescribe B12 specifically unless it’s low.
TCPR: Do you actually see weight loss on metformin? Or does it just slow down the weight gain? Dr. Mago: It can do both, but it depends on when it’s started. There is significant data to suggest metformin works better when it’s started early. Too often we wait 1–2 years, and by that time the patient may have gained 30–40 pounds. Once insulin resistance has occurred, it’s harder to treat.
TCPR: When do you start it? Dr. Mago: A good time to consider metformin is 1–2 months after starting the antipsychotic. If patients have clearly gained weight after being on the antipsychotic for 4–8 weeks (and especially if they also report a marked increase in appetite), this predicts continued longer-term weight gain. This is when it might be most appropriate to consider metformin—not prophylactically, but without waiting too long.
TCPR: Do your patients ever resist metformin? Dr. Mago: Sometimes they will say to me, “No, I’ll diet and I’ll exercise.” I say, “Listen, why don’t we start the metformin along with those lifestyle changes. It’s not a lifelong decision. After you lose this weight, we can cautiously taper it off.”
TCPR: What if the patient is not gaining weight but you see signs of insulin resistance in the patient’s labs, like a rise in HbA1c. Would metformin be useful there? Dr. Mago: Yes, absolutely, since metformin is routinely used by internists and endocrinologists for the treatment of diabetes, but I would also refer that case to a primary care physician for monitoring and treatment.
TCPR: When we see a patient who’s restless, how do we know that it’s akathisia instead of something else like agitation, mania, or ADHD? Dr. Mago: The key to identifying akathisia is an inner sense of restlessness and an urge to move, regardless of whether the patient is visibly moving around a lot. The presentation can be subtle, but it is fairly common in patients on antipsychotics. I recommend evaluation for possible akathisia in any patient who has restlessness or anxiety while on an antipsychotic. Akathisia can also happen on antidepressants, particularly in older patients, but it is far more common with the antipsychotics.
TCPR: What if the patient looks restless but doesn’t feel it on the inside? Dr. Mago: If the patient is agitated and can communicate clearly that it’s not due to an inner sense of restlessness, it may be something else. But the patient may also have trouble communicating the feeling. Here’s one tip: If a patient on an antipsychotic walks in place or gets up for no reason while talking to me, it’s almost always akathisia.
TCPR: How do you treat it? Dr. Mago: I start with prevention. Clinical experience shows that if you start the antipsychotic at a low dose and increase it gradually, the risk of akathisia goes down dramatically. I was involved in the original trials of aripiprazole (Abilify) for depression, and I saw a lot of akathisia then. Now I see it much less frequently, even with aripiprazole, because I start the medicine much lower, starting aripiprazole at something like half of a 2 mg tablet daily. From there, I’ll raise it every 5–7 days or slower. If a fast response is needed, I’ll start at a little higher—2.5 mg daily—and titrate a little faster. On the other hand, if the patient had a problem with akathisia on another medicine in the past, the problem is likely to occur again, and I’ll start low and go slower.
TCPR: What is your first-line treatment for akathisia? Dr. Mago: Propranolol is a popular choice, but you have to watch for bradycardia with it. Some patients need a high dose of propranolol to treat the akathisia, even up to 240 mg a day, but we have to start low and titrate up. That’s a problem because akathisia is a horrible experience—it even raises the risk of suicide—and we want to treat it quickly. So I’m not hesitant to start a benzodiazepine to provide some symptom relief. There is evidence from two small studies to support the use of benzodiazepines for the treatment of akathisia, particularly clonazepam (Lima AR et al, Cochrane Database Syst Rev 2002;(1):CD001950). I’ll often start with that one until we can figure out a longer-term solution.
TCPR: How do you dose clonazepam and propranolol? Dr. Mago: With clonazepam, I start with a standing dose, something like 0.5 mg twice daily, and give the patient an additional amount to take as needed, like 0.5 mg every 6 hours prn. But I would not have a problem going higher for severe akathisia. With propranolol, I’ll start with an immediate-release form, typically 20 mg 2 or 3 times a day, and then titrate up depending on response and pulse rate. I ask the patient to take a pulse measurement before each dose, and if it’s below 60 bpm, to skip the dose. If the patient is to continue on propranolol, I consider changing to an extended-release form once I know what dose is required.
TCPR: What’s after benzodiazepines and propranolol? Dr. Mago: Mirtazapine has been shown to work for akathisia. There are at least two randomized controlled trials behind it (Poyurovsky M et al, J Clin Psychopharmacol 2003;23(3):305–308). But, here’s a word of caution: At higher doses, beyond 15 mg at night, mirtazapine can cause akathisia instead of treating it.
TCPR: Do you see hair loss on psychiatric medications? Dr. Mago: Yes. Hair loss is a poorly studied side effect but one that’s very disturbing to patients. Hair loss has a lot to do with a person’s romantic identity, so the emotional reaction is very strong. When they see clumps of hair fall out while showering, it freaks them out.
TCPR: How do you know if it’s due to a medication? Dr. Mago: There are other causes, like infections, pregnancy, or hypothyroidism. Sometimes it’s difficult to tell and we need to refer to a dermatologist, but hair loss is also more common with some medications, particularly divalproex (Depakote).
TCPR: Any suggestions for divalproex-induced hair loss? Dr. Mago: Well, one hypothesis is that the hair loss is due to poor absorption of nutrients that are essential for the hair, like zinc, selenium, and biotin. So, there are case reports of treating it by supplementing these vitamins. We don’t know the exact doses from research, but I’ll use zinc 22 mg, selenium 200 mcg, and biotin 10 mg. I prefer the chelated zinc, as it’s easier on the stomach. And here’s an important tip: We must tell patients to take the supplements at a different time than when they take the divalproex because the medicine interferes with absorption of the supplements.
TCPR: Can patients get all three of the supplements in a single multivitamin? Dr. Mago: Not in doses that high, so they have to take all three separately. Now, the interesting thing is that the hair tends to grow back if the supplements work or if the medication is stopped. So there is some hope. It’s not like their hair follicles have been destroyed.
TCPR: What about hair loss with other medications? Dr. Mago: It can also happen with lithium and the antidepressants. With lithium, the most important thing to do if hair loss is reported is to check the TSH because lithium-induced hypothyroidism could be the cause of the hair loss. But, lithium can also cause hair loss independent of hypothyroidism. We don’t know what to do for hair loss on medications other than divalproex. Some people use zinc, selenium, and biotin, but in my experience that strategy has the best results with divalproex. We should consider referring the patient to a dermatologist for evaluation rather than assuming that the psychotropic medication is causing the hair loss.
TCPR: Why is it important to address orthostasis? Dr. Mago: The most important problem with orthostasis is falls, leading to fractures. Fractures in older adults can lead to serious complications. Orthostasis can happen even before the patient complains of dizziness, so these falls can be unexpected.
TCPR: Which medications tend to cause it? Dr. Mago: Those with alpha blocker qualities like trazodone and some antipsychotics (risperidone, quetiapine, clozapine) are particularly likely to cause orthostatic hypotension. But, other medications like tricyclic antidepressants, MAO inhibitors, clonidine, and even benzodiazepines can cause it as well. The thing to do is to measure it, particularly when a patient has underlying risk factors: older age, heart disease, or taking blood pressure medications, diuretics, or other alpha blockers. Measure patients’ blood pressure after they have been sitting for at least 5 minutes. Then have them stand up, wait 2 minutes, and measure again. If the systolic pressure falls by 20 mmHg or more, then they clearly have orthostatic hypotension. But, in my experience, some patients may be symptomatic even if the drop in systolic blood pressure on standing up is between 10 and 20 mmHg.
TCPR: How do you manage it? Dr. Mago: First, the basics: Patients should stay hydrated and rise slowly when standing, especially from bed. They should hang their legs over the side of the bed, wait a minute, then stand up cautiously while holding on to something. If they feel dizzy, sit back down. I tell them “You need to sit down immediately if you’re dizzy, even if it’s embarrassing and you’re in public.”
TCPR: What else do you do for orthostasis? Dr. Mago: I may use compression stockings or abdominal binders. These keep blood pressure from falling drastically. The abdominal binders tend to be more effective.
TCPR: How do patients use those? Dr. Mago: An abdominal binder is a flat material that wraps around the abdomen, with Velcro straps to hold it together. It works by exerting gentle compression on the veins; it’s not too tight. Patients need to put it on before getting out of bed, because that’s when the risk of falls is greatest. They don’t need to sleep with the binder on, but they need to make sure they put it on before getting out of bed.
TCPR: Do people look thinner with these binders? Dr. Mago: Ha, ha, yes they do. That’s a secondary advantage. The only problem is the binder may show if they are wearing tight clothes. It’s like a broad belt—about 6–8 inches wide.
TCPR: Do you ever use medications to treat the orthostasis? Dr. Mago: There are some options, like alpha agonists and fludrocortisone, which causes fluid and salt retention. But these are tricky to use, so I’d generally refer to the primary care physician.
TCPR: Final question. What’s a common mistake you see in the management of side effects? Dr. Mago: One is prescribing anticholinergics like benztropine (Cogentin) for akathisia or tardive dyskinesia. It doesn’t treat those, but it can help parkinsonism on antipsychotics. The other is more about mindset. Clinicians tend to underestimate how common and significant side effects are. Patients will vote with their feet, and the risk of non-adherence is high. For example, two-thirds of patients stop their antidepressant within six months of starting it. So recognizing and treating side effects is very important. Another myth is that talking to patients about side effects will cause patients to have them, as if by suggestion. There is research on this. It turns out that education does cause patients to tell us more about their side effects, but it also makes them less likely to stop their medication.