Which type of antipsychotic medication is most likely to produce extrapyramidal effects?

The term "extrapyramidal effects" describes involuntary movements that you cannot control. These side effects are most common when taking antipsychotic medications?

When you experience extrapyramidal effects, movements that were once voluntary happen without your control. Examples of extrapyramidal effects include:

• Akathisia: Feeling restless like you can’t sit still. You may have the urge to tap your fingers, fidget, or jiggle your legs.
• Dystonia: When your muscles contract involuntarily. It can be painful.
• Parkinsonism: Symptoms are similar to Parkinson’s disease. You may have a tremor, difficulty finishing thoughts or speaking, and stiff facial muscles. ‌But while a loss of nerve cells causes Parkinson’s disease, the medication causes Parkinsonism.
• Tardive dyskinesia: Facial movements happen involuntarily. You may make a sucking or chewing motion with your mouth, stick out your tongue, or blink your eyes a lot. 

What Are Antipsychotic Medications?

‌Doctors prescribe antipsychotic medications to treat psychosis. Mental health conditions in this category can lead to delusions or hallucinations. Many psychosis disorders are not curable.

‌Antipsychotic medications work because they have dopamine-blocking agents, which can lead to extrapyramidal effects.

How Are Extrapyramidal Side Effects Diagnosed?

Often other people notice involuntary movements before you do. If you take an antipsychotic medication, talk to your loved ones and close friends about the potential side effects. They may be able to help you identify extrapyramidal effects early on.

You can also be more aware of your movements. Do you suddenly find yourself fidgeting or moving more than usual? What happens when you try to stop or control the movements? If you have concerns about anything new you experience, talk to your doctor.

When you talk to your doctor, they may ask about the specific signs of extrapyramidal effects that you, your friends, or your family observe. They may also ask questions about when you or your loved ones first noticed the symptoms. Your doctor wants to make sure these symptoms weren’t present before starting your antipsychotic medication.

How Are Extrapyramidal Side Effects Treated?

Extrapyramidal symptoms caused by medication aren’t usually treated separately. Instead, your doctor may try a lower dose or a completely different medication.

In some cases, a doctor may prescribe lipophilic beta-blockers, benzodiazepines, or anticholinergics to lessen the side effects of antipsychotic medications.

Antipsychotics

Antipsychotic medications also play a prominent role in the chemical restraint of the violent ED patient. These medications include the older “typical” (or “classic”) antipsychotics and the newer “atypical” antipsychotics. Although the precise mechanisms of action are unclear, typical antipsychotics appear to strongly block brain dopamine receptors, whereas the atypical antipsychotics less strongly and more specifically antagonize dopamine and serotonin receptors.34,35 Both classes of antipsychotics have variable effects on other receptors, such as the adrenergic, cholinergic, and histaminic receptors. The typical antipsychotics can be categorized in terms of their “potency,” a description referring to the relative dosing of the medication and generally predictive of its side effect profile. The incidence of sedation, hypotension, and anticholinergic side effects is higher with the low-potency antipsychotics, whereas the incidence of extrapyramidal symptoms is greatest with the high-potency antipsychotics. Low-potency antipsychotics include chlorpromazine (Thorazine) and thioridazine (Mellaril), medium-potency antipsychotics include loxapine (Loxitane) and molindone (Moban), and high-potency antipsychotics include haloperidol (Haldol) and droperidol (Inapsine).

Of the older typical antipsychotics, the butyrophenones—haloperidol and droperidol—have been widely used in the emergency setting. Haloperidol is the most frequently administered antipsychotic to control the agitated ED patients.36 It is available in oral, IM and IV preparations, although the commonly used IV route of administration is not approved by the U.S. Food and Drug Administration (FDA). Haloperidol is generally given in 2.5 mg to 10 mg IM doses (often 5 mg IM for the severely agitated average sized adult), with half doses administered to elders followed by repeated dosing every 20 to 60 minutes as needed. Effects are usually seen within 30 minutes by the IM route, and the average patient typically requires fewer than three doses for the desired clinical effect.37

Droperidol has been commonly used at doses of 2.5 to 10 mg IM and 2.5 to 5 mg IV in a manner similar to haloperidol to control the agitated or combative patient.38 Compared with haloperidol, droperidol appears to more rapidly reduce agitation at equal IM dosing, has a shorter duration of effect, more sedation, a larger incidence of orthostatic hypotension, and a lesser incidence of extrapyramidal symptoms. When compared with midazolam 10 mg IM, droperidol 10 mg IM appears to have an equally rapid onset of action and requires fewer additional doses for sedation.39 The clinical use of droperidol decreased markedly after it was given a controversial black box warning in 2001 by the FDA for concern of QTc prolongation and torsades de pointes.

Monotherapy with atypical antipsychotics for obsessive-compulsive schizophrenia

Typical antipsychotic agents seem to be of limited therapeutic value for patients with OC-SCZ presumably due to their limited serotonergic properties.70 A majority of reports to date indicate that atypical antipsychotics with their serotonin/dopamine antagonism might induce de novo or aggravate preexisting OC symptoms in schizophrenia patients. Nevertheless, there is preliminary evidence indicating that monotherapy with some atypical antipsychotics may attenuate OC symptoms, pointing toward a potential bidirectional (alleviating vs. provoking) effect on OC symptoms in schizophrenia. Thus, olanzapine was efficacious in ameliorating both psychotic and OC symptoms in a large-scale randomized study in young patients with recent-onset schizophrenia-spectrum disorders.71 By the end of a 6-week trial, olanzapine (mean dose 11.3 mg/day) but not risperidone (mean dose 3.0 mg/day) was associated with a meaningful decrease in the severity of OC symptoms (YBOCS, -2.2 vs.-0.3, z = -2.651, P < .01).

Similarly, in a 6-week, open-label, flexible-dose trial, monotherapy with aripiprazole (10–30 mg/day) resulted in a meaningful clinical improvement of OC symptoms in schizophrenia patients who were partially responsive to a prior exposure to either typical or atypical antipsychotic agents.72 Even modest improvement of functioning, due to improvement in OC symptoms, as in this study, might be clinically meaningful for schizophrenia patients. In addition, amisulpride (not currently available in the United States) may effect amelioration of OC symptoms in schizophrenia patients.73–75 Although the underlying mechanism of this positive effect of antipsychotics on OC symptoms is unclear, it could be related to differing serotonergic effects. Notably, aripiprazole is distinguished by its partial dopamine agonism coupled with a low 5-HT2 to D2 affinity ratio and a low 5-HT1A receptor occupancy.76 Amisulpride is distinguished by its highly selective dopamine D2/D3 receptor antagonism and a minimal affinity for the 5-HT2A receptor.77

First-Generation (“Typical”) Antipsychotics

Examining representative first-generation antipsychotics, it has been shown that roughly a 65% occupancy of striatal D2 receptors is necessary for antipsychotic efficacy, whereas neurological side effects emerge when D2 occupancy levels exceed approximately 80%.27 Among the conventional antipsychotics, low-potency agents (such as chlorpromazine) have relatively low affinity for the D2 receptor and hence require higher doses (roughly 50-fold greater than haloperidol). In addition, they are less selective for D2 receptors and so are associated with a wider range of side effects, including orthostatic hypotension, anticholinergic side effects, sedation, and weight gain (Box 42-1). Perphenazine, which was the conventional anti­psychotic selected to represent this class in the CATIE study, is a mid-potency agent that requires doses roughly three-fold greater than are necessary with haloperidol. High-potency conventional agents (such as haloperidol and fluphenazine) are more selective for D2 receptors and more likely to produce EPS, such as acute dystonias, parkinsonism, and akathisia. Because affinity for the D2 receptor is readily measured and is inversely correlated with the typical therapeutic dose for each compound, conversion ratios to calculate equivalent dosing between conventional agents, typically expressed in “chlorpromazine equivalents,” can be calculated (seeTable 42-3).

Haloperidol is available for parenteral (including intravenous [IV]) administration, and both haloperidol and fluphenazine are available in long-acting injectable depot preparations. Although considerable inter-individual variability exists, daily oral doses of haloperidol between 5 and 15 mg are adequate for the large majority of chronic patients; increasing the dose further may only aggravate side effects without improving antipsychotic efficacy. IM and IV administration require roughly half the dose of oral doses. Great care should be taken with the elderly, in whom 0.5 to 2 mg of haloperidol at bedtime may often be sufficient. If a patient has not previously received antipsychotic medication, it is best to start at a low dose before arriving at a standard therapeutic dose which is between 1 and 4 mg orally. A large number of studies have indicated that an optimal response with haloperidol generally corresponds with trough serum concentrations between 5 and 15 ng/ml,28 although clinical titration remains the most reliable approach in most situations. In the setting of serious medical illness and delirium, particularly if other medications with anticholinergic or hypotensive side effects are administered, haloperidol is often used. Patients need to be monitored for torsades de pointes if haloperidol is given IV.29

The mid-potency antipsychotic loxapine is available as a rapidly-acting aerosolized preparation for inhalation to manage agitation in the setting of psychosis or mania.30 It shows efficacy within 10 minutes after inhalation and might obviate the need for IM administration of an antipsychotic to patients who need rapid tranquilization.

Pharmacological Method

The first-choice agents to treat delirium are typical or atypical antipsychotics. Haloperidol is a dopamine receptor antagonist that acts centrally to decrease hallucinations and symptoms of delirium. Side effects include prolonged QT interval, extrapyramidal side effects, and neuroleptic malignant syndrome. The admiration dose of haloperidol should be determined individually according to the age of the patient and the severity of the agitation. For elderly patients, it is preferable to start with 0.25–0.5 mg and carefully titrate the dose of medication. High doses of >4.5 mg/day are associated with increases in the incidence of adverse effects.37 On the other hand atypical antipsychotics have similar effect on treatment such as risperidone, quetiapine, ziprasidone, and olanzapine. This class of medication has less extrapyramidal side effects and is not associated with anticholinergic activity.38–40 However, in elderly patients their use can lead to increased mortality according to Beers criteria (AGS 2015).

Typical or first-generation antipsychotics

Phenothiazines were the first group of antipsychotics to be developed but are used less frequently now. Chlorpromazine (100–1000 mg daily) is the drug of choice when a more sedating drug is required. Trifluoperazine is used when sedation is undesirable. Fluphenazine decanoate is used as a long-term prophylactic to prevent relapse, as a depot injection (25–100 mg i.m. every 1–4 weeks).Butyrophenones (e.g. haloperidol 2–15 mg daily) are also powerful antipsychotics, and are used in the treatment of acute schizophrenia and mania. They are likely to cause a dystonia and/or extrapyramidal adverse effects, but are much less sedating than the phenothiazines.

Options in Choreoathetoid TD.

Because TD appears to be less common with the atypical antipsychotics, many patients on typical antipsychotics have been switched to one of the four approved atypicals with the idea that TD might also be managed to some degree. When such a strategy is adopted, use of clozapine should be reserved for the last, for reasons cited earlier. Increasingly, the atypicals are being used as first-line agents to treat psychotic conditions, but the risk of TD still exists.

Therefore, other treatment options still must be entertained. Oxidative stress has been an interest in TD as elsewhere in neurology: Vitamin E, at dosages of 1600 IU/day, is advocated, but its efficacy is unclear. Agents that augment γ-aminobutyric acid (GABA) neurotransmission are popular, including not only the benzodiazepines (particularly clonazepam and diazepam) but also valproic acid, and, uncommonly, γ-vinyl GABA. Baclofen, a third GABA-ergic agent, has been used at high dosages, but it sedates and has itself been associated with chorea in a case report. As in tardive dystonia, tetrabenazine and reserpine have been used in difficult cases. High dosages may be needed, and benefits often are delayed for weeks to months. Use of electroconvulsive therapy in TD is controversial: In some reports, it has worsened rather than improved adventitious movements. The benefits of pallidal or thalamic surgeries are theoretically viable but untested.

Antipsychotic augmentation

Double-blind trials in the late 1990s demonstrated efficacy of augmentation of SSRI pharmacotherapy with low-dose typical and atypical antipsychotics in OCD.78,79 A metaanalysis of 9 double-blind, placebo-controlled trials of augmentation with typical or atypical antipsychotics demonstrated their efficacy compared to placebo.10 Approximately one-third of treatment-refractory OCD patients will respond to antipsychotic augmentation. OCD patients with comorbid tic disorders appear to respond particularly well to antipsychotic augmentation. Additional trials have subsequently suggested the efficacy of aripiprazole augmentation.80,81 In general, antipsychotic augmentation should not be considered until two SRI trials of adequate dose and duration have been attempted, because of the more benign side effect profile of the SRIs and the reasonable likelihood of response to extended treatment or a switch to a second agent.

Standard of care

The first line of treatment for schizophrenia is the use of antipsychotic medications that are categorized as either typical or atypical. Typical antipsychotics (e.g., haloperidol, perphenazine, and fluphenazine) primarily block the D2 subtype of dopamine receptors, as described in the “Alterations in dopamine neurotransmission” section. However, blockade of D2 receptors in the nigrostriatal dopamine pathway can result in the development of side effects, including extrapyramidal symptoms (e.g., dystonia, akathisia, cogwheel rigidity, and bradykinesia), and D2 receptor antagonism in the tuberoinfundibular dopamine pathway can raise serum prolactin levels that may lead to side effects of abnormal lactation and irregular menstrual periods in females and gynecomastia in males. Long-term exposure to typical antipsychotics is associated with a 25%–50% risk of developing tardive dyskinesia that involves repetitive involuntary movements such as chewing, protruding the tongue, facial grimacing, and abnormal movements of the limbs.

In contrast, atypical antipsychotics (e.g., clozapine, risperidone, olanzapine, and quetiapine) generally have a lower affinity for the D2 receptor than typicals and block the 5HT2A subtype of serotonin receptors though the overall receptor antagonism profile also differs across atypicals. Consequently, atypicals are less likely to produce extrapyramidal symptoms and tardive dyskinesia and might have greater efficacy for negative symptoms than typical antipsychotics. Clozapine has the highest antipsychotic efficacy relative to all other antipsychotic medications but also carries a greater burden of side effects. For example, clozapine is associated with a 1% risk of agranulocytosis, a potentially life-threatening decrease in white blood cells, which increases risk for infection and necessitates regular monitoring of white blood cell levels. In addition, clozapine blocks muscarinic acetylcholine receptors that can produce constipation, dry mouth, blurred vision, and drowsiness. In contrast, risperidone has a higher affinity for D2 receptors than other atypicals and thus has a higher risk for extrapyramidal symptoms and elevated prolactin levels. Meanwhile, the high affinity of clozapine, olanzapine, and quetiapine for histamine receptors leads to greater risk for sedation and weight gain. Antipsychotic medications, and in particular the atypicals, also increase the risk of developing the metabolic syndrome, which consists of obesity, elevated blood glucose, and cholesterol levels, and high blood pressure, which requires regular monitoring as well. Because the effectiveness of many atypical antipsychotics (excluding clozapine) is generally similar to that of typical antipsychotics, the prescribing patterns of psychiatrists are generally more informed by matching the side effect profiles of antipsychotic medications with the clinical situation of individual patients.

Given the chronic nature of the disorder and the requirement of long-term pharmacological treatment, long-acting injectable antipsychotics (LAIs) are available as an alternative to oral medication. The use of LAIs can be helpful to address symptom relapse, often due to poor adherence of oral medications.97 As both atypical and typical LAIs are available, selection of a particular LAI involves consideration of the effectiveness of prior treatment trials of oral formulations as well as a patient’s prior history of side effect tolerability.98

Additional treatment of schizophrenia involves multiple forms of psychosocial interventions. For example, social skills training in the areas of employment, activities of daily living, and relationships can help improve social functioning. Individual, as well as group, psychotherapy assists in enhancing medication compliance, self-esteem and coping strategies for life stressors. In addition, by focusing on reducing expressed emotion, such as criticism and hostility, in the family setting, family therapy can help lower the risk of relapse and rehospitalization. Optimal management of schizophrenia involves the integration of psychosocial interventions with antipsychotic medications and service coordination such as through an assertive community treatment (ACT) team. An ACT team typically consists of a psychiatrist, a therapist, a nurse, and a licensed social worker, working together all provide a comprehensive treatment approach and assist the patient in accessing community resources. The primary goal of the integrated treatment approach is to reduce the risk of relapse and rehospitalization, enhance medication adherence, and lead to a higher level of functioning.

Evaluation and management

EPS should be suspected if characteristic motor signs are seen, often in the setting of dementia and with or without seizures. Other conditions to be considered include the side effects of typical and atypical antipsychotic medications. Typically, EPS in the setting of dementia is poorly responsive to levodopa [74]. Case reports exist that have shown improvement on levodopa/carbidopa, leading to subsequent improvements in gait and ADLs. In one case, the patient was thought to have idiopathic Parkinson's disease, while the other patient had dementia. Both patients had resting tremors and bilateral symptoms. Evaluation by a neurologist interested in movement disorders is warranted given the impact that EPS has on patient and caregiver quality of life.

Results

Of the 214 patients, 53.8% falling within the range of 18–28 years old and 38.5% falling between 29 and 38 years old. Fifty-two of the patients were on typical antipsychotics, 64 were on atypical antipsychotics, 93 were on mixed treatments in the form of antipsychotics, mood stabilizers, and/or antidepressants, and 5 patients were on other forms of treatments such as hypnotics and anti-epileptics. Many of the patients were smokers (61.1%). The most common level of education was high school level and 50.5% of the patients were employed, mainly in the technical sector. Totally, 175 of the patients had single relationship status while 39 patients were married, only 19 of the 39 married patients agreed to complete the Arabic version of the Marital Satisfaction Inventory.

Statistical analyses showed significant differences between patients suffering from schizophrenia and their experience of orgasm (p = 0.04), sexual satisfaction (p = 0.05), sexual enjoyment (p = 0.005), ability to maintain an erection (p = 0.006), and erection (p = 0.01) measured by the Sexual Behavior Questionnaire. There was a significant negative correlation between sexual enjoyment and age of patients (p = 0.04, r = −  0.76). Sexual excitement and delayed ejaculation had significant correlations with smoking (p = 0.05, r = −  0.73; p = 0.01, r = 0.69, respectively). Table 1 provides further details of these results. When examining the association between treatment and satisfaction of sexual life, only those who were receiving mixed treatment and those on typical antipsychotics, showed a significant association with dissatisfaction in their sexual life. These results are represented in Table 2.

Table 1. Comparison of Sexual Behavior Questionnaire items in psychotic patients (n = 214) and their experience of sexual functioning.

Table 2. Results of Sexual Behavior Questionnaire in schizophrenia patients in relation to drug treatment type. “Others” represent anti-epileptic drugs.

Results investigating sexual dysfunction in married males who completed the MSI, showed that patients were significantly dissatisfied with their sexual life in their marriage, with 50% of them being dissatisfied due to side effects of medication (p = 0.05). A total of 16 out of 19 wives answered both questionnaires provided, 2 wives refused to participate and 1 did not come with her husband in his follow-up sessions. Table 3 shows significant differences between the patients physically (p = 0.03), sexually (p = 0.02), and psychologically (p = 0.005) abusing their wives. Analyses of the responses from the Women Abuse Scale in relation to drug treatment showed significant differences between the 31% and 33% (n = 4) of patients who received mixed treatment are being physically and sexually abusing their wives, respectively. 40% (n = 6) of the same group are psychologically abusing their wives (p = 0.05).

Table 3. Number of patients abusing their wives and the different types of abuse occurring.

Positive correlations were found between mixed drug treatment and mild erectile dysfunction (p = 0.0005, r = 0.87), and sudden onset of erectile function (p = 0.01, r = 0.081). A positive correlation was also found between receiving typical antipsychotic and mild erectile dysfunctions (p = 0.05, r = 0.77). Correlations between receiving typical antipsychotics and sudden onset of erectile function, and between receiving atypical antipsychotics and mild erectile dysfunctions and sudden onset of erectile function were not significant.

Table 4 shows significant differences found in patients with mild erectile dysfunction, sudden onset of erectile dysfunction, erectile dysfunction, with their partner only and presence of morning erection (p = 0.05, 0.02, 0.04, and 0.05, respectively). Table 5 portrays significant differences between different types of erectile dysfunction and sexual dissatisfaction. As well as a significant association between erectile dysfunction and dissatisfaction with the time spent with their wives. Finally, a statistical significance was also found between patients with mild erectile dysfunction and their dissatisfaction with their financial issues (p = 0.04).

Table 4. Comparison of erectile function in the International Index of Erectile Function (IIEF).

Table 5. Correlation of sexual dissatisfaction and erectile function.