Side effects of antipsychotics

The introduction of new antipsychotic drugs over the past 30 years has significantly changed the treatment and prognosis of psychotic disorders. For this reason, alongside efficacy studies, more research is being conducted on the safety and tolerability of these drugs, since side effects are no longer considered uniform or inevitable, and increasingly more studies are being published on their short- and long-term side effects.

Schizophrenia itself carries a higher risk of medical comorbidity (coronary artery disease, hypertension, osteoporosis, etc.), so certain side effects, such as metabolic, cardiovascular, and endocrinological ones, must be given special consideration. Improving these effects helps patients maintain better adherence to treatment, ensuring greater stability and a better clinical prognosis, as well as improved quality of life and functional capacity.

Mechanisms of action of antipsychotics

All antipsychotics share a common antidopaminergic mechanism of action. The differences between antipsychotics lie in their affinity for various dopaminergic and serotonergic receptors, as well as for other subtypes of noradrenergic, cholinergic, and histaminergic receptors.

Antipsychotics are classically divided into two groups: conventional or typical and atypical.

Conventional antipsychotics

These were the first drugs used, starting with chlorpromazine. Their main mechanism of action is the antagonism of D2 receptors, which, when it occurs in the mesolimbic pathways, reduces the dopaminergic hyperactivity that produces the positive symptoms of psychosis. They are very effective drugs, but with the drawback that D2 antagonism also occurs in other pathways with cerebral D2 receptors, causing side effects such as worsening of cognitive and extrapyramidal symptoms, or elevated prolactin levels.

Conventional antipsychotics act on other receptors such as muscarinic cholinergic, histaminergic, and alpha-adrenergic receptors, to varying degrees depending on the drug in question, producing the following side effects:

Cholinergic receptors

• Dry mouth
• Blurred vision
• Constipation
• Dizziness

• Weight gain
• Sleepiness
• Dizziness

• Orthostatic hypotension
• Dizziness

The most common conventional antipsychotics are: chlorpromazine, levomepromazine, flupentixol, fluphenazine, haloperidol, perphenazine, pimozide, sulpiride, thioridazine, trifluoperazine, and zuclopentixol.

Psychosocial approaches to psychosis

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Atypical antipsychotics

Atypical antipsychotics are characterized by producing fewer extrapyramidal effects and appear to be more effective in treating negative symptoms due to a lower dopaminergic effect and a higher affinity for serotonergic receptors.

This group basically consists of the following drugs: clozapine, risperidone, paliperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole, and asenapine. The most important differences between the various antipsychotics are based on their affinity for different receptors and their adverse reaction profiles.

They can be classified according to their mechanism of action:

• Serotonin (5HT2A) and dopamine antagonists: these act on the interaction of these two neurotransmitters. This is the mechanism of action of clozapine, risperidone, paliperidone, olanzapine, quetiapine, asenapine, and ziprasidone.
• D2 antagonists with rapid dissociation: short-term receptor blockades are sufficient to achieve antipsychotic effects, while a stronger binding is needed to produce extrapyramidal effects. This group includes amisulpride.
• Partial D2 agonists: these bind to the D2 receptor only partially, thus providing an antipsychotic effect without producing extrapyramidal effects. Aripiprazole is an example of this.

Metabolic side effects

The most common metabolic side effects are weight gain, hypertriglyceridemia, low HDL cholesterol levels, hypertension, and hyperglycemia. These effects frequently occur together.

This combination of risk factors is called metabolic syndrome and is associated with an increased risk of cardiovascular disease and diabetes.

The most widely accepted definition for metabolic syndrome is:

Criteria for metabolic syndrome (ATP III definition)

A diagnosis of metabolic syndrome is made when 3 or more of the following risk factors are present:

1. Abdominal circumference >102 cm in men and >88 cm in women
2. Serum triglycerides >/=150 mg/dL (>/=1.7 mmol/L)
3. Blood pressure >/=130/85 mmHg
4. HDL Cholesterol 40mg/dL (1.0 mmol/L) in men and 50 mg/dL (1.3 mmol/L) in women
5. Fasting glucose 110 to 126 mg/dL (6.1 to 7.0 mmol/L) (100 mg/dL [>/=5.6 mmol/L] may also be appropriate)

How to explore them and measuring instruments

It is recommended to measure the following parameters:

• Body weight
• Body mass index (BMI) - Weight (kg) / Height ² (Mts)
• Abdominal circumference, which is the index taken into account for the diagnosis of metabolic syndrome.
• Determination of blood pressure (BP)
• The analysis should always include the determination of triglycerides, HDL cholesterol and fasting glucose.

Weight, BMI, and waist circumference should be recorded before starting a new antipsychotic, at 6 weeks, and quarterly thereafter. Blood tests and blood pressure measurement should be performed if a new antipsychotic treatment is initiated, at 6 weeks, at 6 months, and annually thereafter. If a weight increase of more than 5% is found since the last blood test, additional blood pressure, lipid profile, and glucose levels should be measured.

Key points

Women are at greater risk of weight gain, and rates of dyslipidemia in antipsychotic treatment are also higher than in men.

Other predictors of weight gain include a family history of being overweight. Being overweight or obese before starting antipsychotic treatment is also a risk factor.

Younger people receiving treatment also have a higher risk of weight gain due to antipsychotic treatment.

In women, postmenopause is associated with a higher risk of metabolic syndrome.

Tobacco use is very common in patients undergoing antipsychotic treatment and it is necessary to take it into account as an important cardiovascular risk factor.

David Millana

Person affected by a psychotic disorder

"Having a psychotic episode has helped me to get my life back on track and now I feel better than before."

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Sexual and reproductive side effects: hyperprolactinemia

Hyperprolactinemia (HPRL) is defined as levels above 450 mU/L in women and 320 mU/L in men. In women, PRL levels are higher during the second half of the menstrual cycle and increase 10-20 times during pregnancy and lactation. Antipsychotics, in general, are drugs that elevate prolactin (PRL), which is highly relevant due to its effects on reproductive and sexual function and other less treatable medical complications, such as osteoporosis or an increased risk of breast cancer.

Antipsychotics that cause hyperprolactinemia

Conventional antipsychotics are most closely associated with HPRL, and along with risperidone, paliperidone, and amisulpride, they form the group of prolactin-increasing antipsychotics. In contrast, olanzapine and quetiapine have been shown to increase prolactin levels only transiently and mildly, and are therefore considered non-prolactin-increasing antipsychotics, along with the other atypical antipsychotics.

Aripiprazole is associated with a low prevalence of HPRL. As monotherapy, it can even lower prolactin levels below normal.

Most common effects

The most common effects of HPRL are reproductive and sexual, affecting both sexes. Sexual dysfunction (SD) has been described in 30-60% of patients on antipsychotic treatment.

Most common reproductive effects of HPRL in women:

• Galactorrhea
• Menstrual irregularity (oligomenorrhea or amenorrhea). In these cases, serum estradiol levels are usually found in the post-menopausal range (16).
• Infertility secondary to amenorrhea, oligomenorrhea, or anovulatory cycles.
• Hirsutism and acne.

Most common reproductive effects of HPRL in men:

• Infertility, due to hypospermatogenesis.
• Gynecomastia
• Galactorrhea, rarely
• Decrease in muscle mass and body hair.

Sexual effects of AP use more common in women:

• Decreased libido
• Vaginal mucosal atrophy
• Dyspareunia
• Decreased vaginal lubrication

Sexual effects of AP use more common in men:

• Decreased libido
• Erectile dysfunction
• Ejaculatory dysfunction

The antipsychotics aripiprazole and quetiapine are the ones that usually produce the least DS, followed by ziprasidone and clozapine, with olanzapine, conventional antipsychotics and risperidone being the most associated with DS.

It is important to keep in mind that DS has a multifactorial origin, involving the symptoms of the mental illness itself, other effects of medication (sedatives, anticholinergics, antiadrenergics) and the use of alcohol.

Other effects of sustained HPRL include osteopenia and osteoporosis, which can be detected through bone mineral densitometry. Relatively short periods of HPRL can already have significant adverse effects on bone density. It is also currently suggested that prolonged elevation of prolactin (PRL) may predispose individuals to an increased risk of breast cancer and probably prostate cancer.

Key points

Women experience higher prevalence and intensity of PRL elevations during chronic antipsychotic treatment, especially during childbearing age.

When antipsychotics are combined, the effect of the antipsychotic that raises prolactin (PRL) levels usually predominates. Only in the case of aripiprazole can concomitant treatment correct PRL levels and reduce symptoms without the need to discontinue the other drug.

How to explore sexual and reproductive symptoms?

These effects can be detected through interviews and standardized measurement instruments. In this guide, we propose the UKU side effects scale for both sexual and reproductive effects, and the SALSEX and CSFQ sexual effects scales.

Extrapyramidal side effects

Extrapyramidal symptoms are the most easily recognized adverse effects of antipsychotic treatment. These side effects are often very bothersome and a frequent cause of non-adherence to antipsychotic treatment. They are not entirely predictable, as their occurrence depends on the type of medication prescribed, the dosage, and the individual's susceptibility. They are usually attributed to typical antipsychotics, or in cases of high doses of atypical antipsychotics such as risperidone or olanzapine.

Types of extra-pyramidal effects

• Parkinsonian symptoms: include rigidity, tremors, akinesia, and bradykinesia.
• Acute dystonia: characterized by spastic contraction of isolated muscle groups. It frequently occurs after the first doses of medication, and in 90% of cases within the first three days. These reactions therefore have a sudden onset and cause significant discomfort.
  Acute dystonia can affect various parts of the body, but most frequently affects the muscles of the neck, larynx, eyes, and torso. It responds rapidly to anticholinergic or antihistamine medication. Initially, the preferred route of administration is parenteral, followed by oral administration.
• Akathisia : This is defined as physical restlessness. Affected individuals often describe an internal feeling of agitation with an irresistible urge to move various parts of their body. In mild cases of akathisia, the person is able to control their body movements. In severe cases, the person needs to pace while standing and is unable to sit still.
  Effective treatments for akathisia include centrally acting beta-blockers: propranolol 30-90 mg/day. In these cases, blood pressure and heart rate should be monitored.
• Neuroleptic malignant syndrome is characterized by a number of features: rigidity, fever, motor instability, hypertension, and tachycardia. Its onset is usually sudden, often occurring during the first week of treatment or after an increase in the drug dose. It is a rare but potentially fatal side effect of some medications.
• Tardive dyskinesia: This is a disorder of abnormal involuntary movements caused by prolonged use of antipsychotic medication. Involuntary movements are observed, primarily in the orofacial region. It can also affect the following muscle groups:

1. Muscles of facial expression (forehead and periorbital area).
2. Lips and perioral area (difficulty blowing, whistling).
3. Jaw (biting, chewing, lateral movements).
4. Tongue (tongue protrusion, tremor).
5. Limb movements (chorea, athetosis, tremor).
6. Involuntary movements of the forearms, wrists, and fingers.
7. Involuntary movements of the lower legs, ankles, and toes.
8. Trunk movement: involuntary movements of the neck, back and hips (rocking, twisting, contorting, turning).

Tardive dyskinesia is often associated with significant distress and physical discomfort. Treatment options include switching to atypical antipsychotics or reducing the dose of the typical antipsychotic.

Key points

• Parkinsonian symptoms affect adults and older people more and appear gradually.
• Risk factors for acute dystonia include: younger age, male sex, use of high-potency drugs, high doses, and intramuscular administration.
• The factorsRisk factors in neuroleptic malignant syndrome include: acute agitation, younger age, male sex, previous neurological disability, physical illness, dehydration, rapid increase in antipsychotic dose, administration of high-potency drugs, and intramuscular administration.
• Risk factors for tardive dyskinesia include: advanced age, antipsychotic-induced parkinsonian symptoms, female sex combined with postmenopausal status, a diagnosis of affective disorder, associated medical conditions (such as diabetes), and the use of high doses of antipsychotics.

Other side effects

Blood tests: Agranulocytosis

Antipsychotics can cause inhibition of leukopoiesis, which can result in benign leukopenia or, in more severe cases, agranulocytosis.

Neutropenia is defined by a count of 1,500 neutrophils/ ^mm3 , and agranulocytosis by an absolute neutrophil count down to levels of 500 neutrophils/ ^mm3 .

Agranulocytosis is a rare but potentially fatal adverse effect. Clozapine has an incidence of agranulocytosis of 1% and of neutropenia of 3%.

Recommendations

• Before starting treatment, the white blood cell count and the white blood cell differential must be within normal limits.
• Clozapine treatment protocols involve weekly white blood cell count monitoring for the first 18 weeks of treatment and monthly monitoring thereafter. If clozapine treatment is continued and the blood count remains stable after one year, monitoring should be performed at least every four weeks (as well as four weeks after discontinuation). If the white blood cell count falls below 3,000/ ^mm³ or the absolute neutrophil count falls below 1,500/ ^mm³ , the drug should be permanently discontinued and the patient referred to a hematologist.
• Avoid drugs that decrease leukopoiesis
• The affected person should immediately report any symptoms of infection, particularly flu-like symptoms.

Alice

Person with personal experience of psychosis

"I had to build a new version of myself"

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Sedation

It includes both drowsiness and the subjective feeling of dullness.

The drugs that most frequently cause sedation are chlorpromazine, clozapine, olanzapine, and quetiapine. Aripiprazole and amisulpride appear to be the antipsychotics with the lowest incidence.

The sedation produced by some antipsychotics can be used to promote sleep by recommending taking the drug at night.

Anticholinergic effects

The most frequent anticholinergic effects are: cognitive impairment (memory and learning), dry mouth, constipation, decreased sweating, congestion and urinary retention.

Symptoms of anticholinergic toxicity include confusion, delirium, drowsiness, and hallucinations. These symptoms are more likely to occur in elderly or medically debilitated patients.

The drugs with the highest incidence of anticholinergic effects are chlorpromazine, clozapine, and olanzapine. Risperidone, paliperidone, ziprasidone, asenapine, and aripiprazole have minimal or no incidence of anticholinergic effects.

Orthostatic or postural hypotension

It is defined as a sudden drop in blood pressure after a person has been standing for a prolonged period, or when they stand up after sitting or lying down. It is a response to the adrenergic effects of antipsychotics.

Antipsychotics with a high incidence of this side effect include clozapine and quetiapine. Antipsychotics with a low incidence include olanzapine, ziprasidone, and aripiprazole.

Seizures

Generalized tonic-clonic seizures may occur. These can happen during the use of typical antipsychotics, although clozapine is the antipsychotic with the highest incidence of seizures. Antipsychotics with a lower risk include risperidone, ziprasidone, and aripiprazole.

Liver effects

Typical antipsychotics can cause elevated liver enzyme levels and cholestatic jaundice. This usually occurs during the first month of treatment, and in such cases, treatment should be discontinued.

Allergic and dermatological effects

They are quite common, especially with typical antipsychotics.

Cardiac: QT interval prolongation

Prolongation of the corrected QT interval (QTc) (greater than 500 ms) is associated with the occurrence of ventricular arrhythmias, torsades de pointes, and sudden death.

The antipsychotics with the highest risk are haloperidol, chlorpromazine, and ziprasidone. If these drugs are used, the maximum dose should not be exceeded. Aripiprazole has little to no effect on QT prolongation.

Patients should be advised to consult their doctor whenever they are taking concomitant medication, as it is essential to avoid the concomitant use of drugs that inhibit metabolism or excretion, prolong the QT interval, or cause hypokalemia. Hypocalcemia, cocaine abuse, and alcohol abuse also increase the risk of QT prolongation.

This increases with age, and women have a longer QTc interval than men.

As recommendations, it is necessary to:

• Monitor potassium and calcium levels.
• Perform electrocardiogram and measure QT.
• Avoid prescribing if QT is prolonged.

Kidney failure

In cases of renal insufficiency (RI), it is necessary to adjust the dose of the antipsychotic amisulpride, and even avoid it if RI is severe.

If using risperidone, it is recommended to reduce the dose to 50%.

Liver failure

It is recommended to adjust the dose of the antipsychotics risperidone and clozapine if there is underlying liver failure.

Gastrointestinal obstruction

Reactions mimicking gastrointestinal obstruction have been reported. Clozapine should be used with caution if constipating drugs (e.g., antimuscarinics) are being used or if there is a history of colon disease or bowel surgery.

It is recommended to monitor for constipation and make dietary recommendations.

Nursing approach for people on antipsychotic treatment

Nurses play a vital role in the multidisciplinary care of people with psychotic disorders and in assessing the adverse effects of their treatment.

Regarding the assessment of adverse effects of antipsychotics, nurses work from a collaborative role and apply the following nursing interventions (NIC):

• Teaching: Prescribed Medications.
• Administration of medication via oral and/or parenteral route
• Surveillance.

The use of specific assessment scales for the detection of different adverse effects can be very useful to improve treatment compliance, the safety of the person being treated and to guarantee the quality of care.

The following tables summarize the main side effects of the most commonly used atypical antipsychotic drugs, as well as general recommendations for monitoring antipsychotic side effects by nurses.

Summary of side effects of the most commonly used atypical antipsychotics

Physical condition and detection of concomitant physical diseases

Recommended scales for assessing general adverse effects