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Day #15: General Side Effects of Antipsychotics

Today we will continue our discussion about potential side effects of the antipsychotic group of medications. We already covered EPS and NMS and today we are going to provide a more general overview of common side effects that are important clinically as well as frequently tested on licensing exams.

Today's Content Level: Beginner; Intermediate

Why so many side effects?

•When a patient ingests an antipsychotic medication, there is a lot more going on in the body than simply dopamine (D2) blockade in the mesolimbic system.

•Some side effects are a result of changes in dopamine regulation (eg.,EPS, NMS, prolactin secretion, cognitive symptoms).

•Other side effects occur due to effects on other receptors throughout the body (alpha adrenergic, histaminergic, cholinergic, etc.).

•Side effects are a common reason for treatment discontinuation particularly when efficacy is poor.

•Below we will discuss important side effects of this class of medications. Some of these are common and some are rare but important to know about. We will talk about weight gain, metabolic syndrome, and EKG changes in detail and then briefly hit on the other side effects.

Weight gain

•This is a well-known and, unfortunately, common side effect of antipsychotics.

•Suggested mechanisms: blocks histamine (H1), serotonin (5HT2C), and dopamine (D2) receptors. It has also shown to increase serum leptin and leads to leptin desensitization. Leptin is a hormone responsible for the feeling of satiety after eating meals. 1

•Weight gain seems to result from increased food intake and reduced energy expenditure. 2

All antipsychotics have been associated with weight gain, although mean weight gained varies substantially between drugs.

•High risk: Clozapine, Olanzapine

•Moderate risk: Chlorpromazine, Iloperidone, Quetiapine, Risperidone, Paliperidone

•Low risk: Amisulpride, Asenapine, Brexpiprazole, Aripiprazole, Haloperidol, Lurasidone, Ziprasidone 3

•Prevention and treatment of the weight gain and associated metabolic side effects are extremely important. Also contributes to high rates of hypertension seen in this population.

•Rapid weight gain in early treatment (≥5% above baseline after 1 month of treatment) strongly predicts long‐term weight gain and should prompt consideration of preventative or remedial measures. 4

Treatment options: (5)

  • Behavioral interventions: improve diet and increase physical activity

  • Switching drugs (less risk of weight gain) (aripiprazole, ziprasidone, lurasidone). Risk of relapse of psychotic symptoms.

  • Addition of metformin (500-2000mg/day). Now considered the drug of choice for prevention and treatment of antipsychotic-induced weigh gain although GLP-1 agonists may ultimately prove more effective and better tolerated.

  • Addition of aripiprazole to existing treatment. Evidence when used as adjunct to clozapine or olanzapine.

  • Other drugs under investigation: Amantadine, Orlistat, Reboxetine, Topiramate, Zonisamide

Other Metabolic Syndrome Features

•In addition to weight gain, antipsychotics have known effects on plasma lipid levels, glucose levels, and diabetes.

•Dyslipidemia is an established risk factor for cardiovascular disease along with obesity, hypertension, smoking, diabetes, and sedentary lifestyle.

•While cholesterol levels can rise, the most profound change is increased triglycerides. Olanzapine and Clozapine are particularly harmful in this regard and have been shown to increase levels by 40% over short (12 weeks) and medium (16 months) timelines. 8

•Treatment of dyslipidemia: Options include switching to another antipsychotic less likely to cause this problem (eg, ziprasidone or aripiprazole), dietary/lifestyle changes, and/or treatment with statins.

•Schizophrenia is associated with relatively high rates of insulin resistance and diabetes even in spite of the risk added by antipsychotic use. 9 This can also occur in the absence of weight gain.

•As with dyslipidemia, olanzapine and clozapine appear to be most strongly linked to increased plasma glucose, impaired glucose tolerance, diabetes, and diabetic ketoacidosis. Risperidone, quetiapine, and other drugs have also been implicated. Ziprasidone, aripiprazole, amisulpride, lurasidone, and asenapine appears not to alter glucose homeostasis and are recommended for those with a history or predisposition to diabetes. 10

•Treatment of diabetes: Options include switching to drug with low or minimal risk (aripiprazole, ziprasidone, lurasidone) and the addition of GLP-1 agonists or metformin. Refer the patient to primary care for additional diabetes management.

ECG changes

•Some antipsychotics block cardiac potassium channels and are linked to the prolongation of the cardiac QT interval. This is a risk factor for the ventricular arrhythmia torsades de pointes which is often fatal.

•Overall risk is dose-related. Absolute risk is low.

•Risk increases beyond normal limits (440ms for men, 470 for women) however stronger evidence links values over 500ms to be clearly increased risk. 6

•No effect: Brexpiprazole, Lurasidone

•Low effect (<10 ms): Aripiprazole, Asenapine, Clozapine, Perphanazine, Fluphenazine, Olanzapine, Paliperidone, Risperidone, Loxapine

•Moderate effect (>10 ms): Chlorpromazine, Haloperidol, Iloperidone, Quetiapine, Ziprasidone

•High effect (>20 ms): any IV antipsychotic or drug combination in doses exceeding recommended maximum

•Note that effect on QTc may not necessarily equate directly to risk of torsades de pointes or sudden death, although this is often assumed. 7

•Consider other patient risk factors for QTc prolongation and arrhythmia: Other QT prolonging medications (see crediblemeds for latest info), Cardiac (Long QT, bradycardia, ischemia, LVH), Metabolic (hypokalemia/magnesemia/calcemia), extreme physical exertion, shock, anorexia nervosa, extremes of age, and female gender.

Other Side Effects

Dopamine (D2) blockade in the Tuberoinfundibular pathway -> stimulates prolactin secretion -> (women) breast discharge [galactorrhea], amenorrhea, sexual dysfunction -> (men) enlargement of breast tissue [gynecomastia], sexual dysfunction. This is most common with first-generation antipsychotics (FGA's), risperidone, asenapine, and paliperidone. Treat by switching to quetiapine or aripiprazole. This same mechanism can lead to changes in bone metabolism and increase incidence of osteoporosis and risk of fractures if taken for prolonged period of time. Of note, sexual dysfunction is also common in those with schizophrenia due to the underlying condition, metabolic effects, as well as affects on dopamine, serotonin, acetylcholine, and alpha adrenergic receptors.

Alpha-1 Adrenergic blockade -> dizziness, postural hypotension, sedation. Typically presents during the initial dose titration period but can persist. Highest with clozapine, quetiapine, and iloperidone.

Histamine blockade -> weight gain, drowsiness.

Cholinergic blockade-> dry mouth, constipation, blurry vision, urinary retention, confusion. Constipation is a frequent complaint. Clozapine, in particular, can be extremely constipating, decrease GI motility, and is associated with a risk of toxic megacolon. 11 Patients should be on a bowel regimen and frequently asked about bowel movement habits.

Cognitive Impairment + Increased Negative symptoms: schizophrenia is associated with these symptoms in spite of pharmacology, however there are two drug interactions that worsen this. 1) Dopamine (D2) blockade in the mesocortex. 2) Cholinergic blockade. Symptoms include avolition, anhedonia, low motivation, poverty of speech, and isolation.

Hyponatremia: Can occur via 1) Water intoxication (increased thirst drive). 2) Drug-induced syndrome of inappropriate antidiuretic hormone (SIADH). Can differentiate via urine labs (osmolality, sodium). 3) Severe hyperlipidemia and/or hyperglycemia leading to 'pseudohyponatremia'.

Pneumonia: Associated with 70-100% increase risk of pneumonia across a range of diagnoses. 12 Mechanism not known but possiblities include sedation, dystonia/dyskinesia, dry mouth, and increased aspiration risk.

Venous thromboembolism: Absolute risk is small but does probably increased the risk by about 50%. 13 Proposed mechanisms include sedation, obesity, hyperprolactinemia, elevated phospholipids antibodies, platelet aggregation, and elevated plasma homocysteine.

Black box warnings: The FDA has issued a black-box warning of increased mortality risk with atypical antipsychotics in patients with dementia (relative risk 1.6 to 1.7) vs placebo. The mortality rate in antipsychotic-treated patients was about 4.5%, compared with about 2.6% in the placebo group. Most deaths were cardiovascular and cerebrovascular (heart failure, stroke, sudden death) or infectious (pneumonia).

Catatonia: Syndrome of abnormal movement and behavior that arises due to medical illness, disturbed mental state, or pharmacologic adverse effect including antipsychotics. We will not cover this syndrome at this point, but we will discuss this in a later section under major neurocognitive disorders.

Seizure threshold: All antipsychotics lower the seizure threshold (increase risk of seizures), although clozapine confers the greatest risk. 14


Scales: A common scale used to monitor side effects of antipsychotics is the Glasgow Antipsychotics Side-effect Scale (GASS). Fore a more detailed/comprehensive scale look into the Antipsychotic Non-Neurological Side-Effects Rating Scale (ANNSERS). Scales for EPS as discussed here.

Medical monitoring: Due to the aforementioned side effects; regular medical monitoring is essential for these patients. Regularly obtain the following data:

Height, weight, BMI, Waist circumference: baseline, monthly x 3 months, and at least every 6 months

Blood pressure, pulse: baseline, monthly x 3 months, and at least every 6 months

Lipids: baseline, every 3 months for a year, and then annually.

Fasting blood glucose or Hemoglobin A1C: no clear guidelines, baseline, every 3 months for a year, and then annually.

Prolactin: this is controversial, baseline for higher risk medications and prn if symptomatic

EKG: all pts on high doses should have baseline, when steady-state serum levels reached, after each dose increment, and then every 6-12 month


This was a heavy topic. I broke my own rule because this is a 6-minute post. I definitely recommend re-visiting this and we will make sure to review this content in our "week in review" on Monday. Remember that the exact side effect profile is drug-specific. Always look up this information before prescribing a drug. Next week we will cover some of the classic or "don’t miss" side effects of specific drugs. Have a great weekend!

Resources for today's post include:

And the articles embedded in the post.

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