Antipsychotics and the Likelihood of Weight Gain

Weight gain can be a difficult side effect for people taking antipsychotic medications. Not all drugs are equally likely to cause weight gain, and this post looks at the findings from a study published in 2020 in The Lancet Psychiatry that compared the potential for weight gain with different antipsychotics.

The link between antipsychotics and weight gain

To start, let’s talk about why antipsychotics can cause weight gain. There are multiple different neurotransmitter pathways that can play a role in weight and metabolism. These pathways involve different types of neurotransmitters and specific receptor types that may be agonized (boosting their activity doing whatever it is they normally do) or antagonized (blocking/reducing their activity).

Antipsychotics across the board are characterized by their antagonist activity at D2 dopamine receptors, and atypical (newer) antipsychotics also antagonize 5HT2a serotonin receptors, but besides that, all of the antipsychotics also interact with a variety of other receptor types, and the exact mix varies from one drug to another.

The likelihood of a medication causing weight gain depends on how involved the medication gets in a few particular pathways, which include:

• histamine and H1 receptors
• serotonin and 5HT2c receptors
• epinephrine and alpha-1 receptors
• acetylcholine and M3 receptors

Antipsychotics can also increase cholesterol and triglycerides and increase insulin resistance and diabetes risk. Together, these effects, along with hypertension, are known as metabolic syndrome, and people taking atypically antipsychotics should be assessed for this a couple of times per year. Atypicals are more likely than typicals to contribute to metabolic syndrome.

Weight gain

I’ve omitted a few of the less commonly used drugs that were mentioned, but the drugs that were associated with weight gain, listed from the most weight gain to the least, were:

• clozapine
• olanzapine
• quetiapine
• risperidone, paliperidone
• asenapine
• brexpiprazole
• flupenthixol
• amisulpride
• cariprazine
• lurasidone
• aripiprazole
• fluphenazine
• haloperidol (on average, people lost some weight)
• ziprasidone (on average, people lost some weight)

Cholesterol and blood glucose

Clozapine, olanzapine, and quetiapine were all linked to increases in cholesterol and triglycerides. Lurasidone, ziprasidone, and cariprazine were less likely than placebo to be associated with an increase in cholesterol.

Clozapine was associated with a clear increase in blood glucose. Smaller increases were seen with cariprazine, olanzapine, haloperidol, and aripiprazole.

All of these findings are averages, and for a given individual, a lower-risk drug may end up causing more problems than a higher-risk drug, or a drug that’s generally associated with weight loss may cause weight gain. All of our bodies are a little different, so there’s variability in how we respond.

What to do with this information

The key issue is what works in treating the illness. Clozapine is hands down the worse culprit for metabolic syndrome, but at the same time, it’s also hands down the most effective antipsychotic there is, especially for people who don’t respond well to other drugs. Plus it’s the only antipsychotic that can improve tardive dyskinesia (an antipsychotic-induced involuntary movement disorder).

Changing medication to reduce metabolic effects may be an option for some people if you can find something that works adequately.

Where medication change isn’t an option, metformin (a diabetes medication) or topiramate (an anticonvulsant) are sometimes used to offset some of the weight gain. Adding on extra medication to manage side effects isn’t ideal, so they’re not used routinely, but they’re options, especially for people who are on clozapine.

My own experience

I’ve gained a lot of weight on quetiapine, but my cholesterol, triglycerides, and blood glucose have been fine thus far. I’ve also tried olanzapine and aripiprazole in the past, and I suppose I could fuss around trying to find something else that would work but not have metabolic effects, but I just can’t be bothered. I can live with my weight. I have no desire to screw up my med regimen and make things worse.

If you take an antipsychotic, have you experienced weight gain or any other metabolic side effects?

Reference

Pillinger, T., McCutcheon, R. A., Vano, L., Mizuno, Y., Arumuham, A., Hindley, G., … & Howes, O. D. (2020). Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: A systematic review and network meta-analysis. The Lancet Psychiatry, 7(1), 64-77.