Psychotic disorders are common debilitating disorders associated with disturbances in perception, emotion and thought. In India, 0.4% of the population is believed to suffer from schizophrenia and other psychotic disorders.[1] Antipsychotics are the mainstay of treatment for these disorders.[2] The discovery of Chlorpromazine in 1952 for treatment of psychotic disorders was the major landmark in the history of drug treatment in psychiatry.[3] This was followed by discovery of various other drugs effective for treatment of psychosis. These drugs, however, had a common adverse effect of extrapyramidal symptoms (EPS). These symptoms include acute dyskinesia, acute dystonia, akathisia, tardive dyskinesia, drug-induced Parkinsonism and neuroleptic malignant syndrome (NMS) (shown in Table 1).[45] At one stage, the development of EPS was considered essential for antipsychotic action. However, introduction of Clozapine in European markets in early 1970s laid these claims to rest.[6] A whole generation of antipsychotics developed after this were associated with significantly lower rates of EPS. This was considered a major advance in the field of psychopharmacology with claims of superiority in terms of effectiveness and reduced side effects, combining serotonin and dopamine antagonism.[7] These drugs include Risperidone, Olanzapine, Quetiapine, Ziprasidone, Aripiprazole etc.[8] Clinical observation and research evidence has found significant differences between second-generation antipsychotics (SGAs) as a drug class in terms of EPS.[9]
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Table 1: Extrapyramidal symptoms (EPS) caused by antipsychotic medications
Despite this, many clinicians routinely use anticholinergics prophylactically with antipsychotics. One study from Bahrain found that almost two thirds of patients were prescribed anticholinergics along with antipsychotics.[10] This is despite distressing adverse effects associated with anticholinergics like dry mouth, urinary disturbances, constipation, cognitive impairment, worsening of tardive dyskinesia and delirium.[11] This paper aims to explore the rationale for prophylactic use of anticholinergics with antipsychotics. We review the scientific literature for such use and summarize the major practice guidelines on the subject.
Why are anticholinergics prescribed with antipsychotics?
Anticholinergics are prescribed ostensibly for treatment or prophylaxis of EPS induced by antipsychotics. Of these symptoms, acute dystonia and akathisia develop within hours of initiation of antipsychotic medications. Drug-induced Parkinsonism develops over weeks, while Tardive Dyskinesia takes months to years to develop.
Acute dystonic reactions are effectively treated with anticholinergic drugs. Symptom resolution is dramatic within 10 to 30 min of administration of parenteral anticholinergics.[12] A Cochrane review conducted in 2006 found that there was no reliable data to recommend or refute the use of anticholinergics in neuroleptic-induced akathisia.[13] A systematic review on treatment considerations for antipsychotic-induced akathisia reported that before considering adjuvant medications for treatment one must consider dose reduction and cessation or switching of the antipsychotic.[14] It further added that considering the limitations of the available evidence on anticholinergic medications and the risk of cognitive and anticholinergic adverse effects with these drugs, anticholinergic medications should not be routinely used for the treatment of akathisia.[14] A Cochrane review conducted in 2018 reported that it was uncertain that the use of anticholinergics is useful in patients with tardive dyskinesia.[15] A review of literature also suggests that anticholinergics should be avoided in dyskinesia as they can likely worsen the symptoms.[16] Literature also suggests that anticholinergics may be efficacious in treatment of drug-induced parkinsonism; however, it recommends that use should be short-term particularly in elderly.[1617]
Do SGAs cause significant EPS?
Extra Pyramidal Symptoms are common side effects of most FGAs. EPS also occur with SGAs, although in significantly reduced rates as reported in a meta-analysis of efficacy and safety of FGAs vs. SGAs. In this meta-analysis, pooled SGAs produced significantly less EPS compared to FGAs (effect size of –0.43, P < 0.001).[18] A number of predisposing factors have been identified for this increased risk like high-dose antipsychotic use, a past history of extrapyramidal symptoms and medical comorbidity. In comparative studies of FGAs and SGAs, the choice of a first-generation comparator significantly influences the results.[19] Within SGAs also, a spectrum of propensity to cause EPS has been found. Lurasidone and Risperidone on one end of the spectrum cause more EPS, while Clozapine on the other has least EPS causing potential.[220] EPS causing potential of different SGAs correlate with their D2 antagonism [Figure 1].[19] One Cochrane meta-analysis reported highest rates of movement disorders with L-sulpiride among SGAs. In the same study, Quetiapine (1.4%) and Olanzapine (1.6%) had lowest prevalence estimate of dystonia.[21]
Figure 1: D2 receptor binding affinity of selected antipsychotics in terms of inhibition coefficient (Ki).
Low Ki values indicate higher binding affinity and thus chances of EPS.[
22]
Available Recommendations regarding use of anticholinergics with antipsychotics
A number of clinical guidelines based on sound scientific evidence are available to guide clinicians in their management of patients with Schizophrenia and other psychotic disorders. These guidelines also talk about management of any treatment emergent adverse effects. Important clinical practice guidelines include those from British Association of Psychopharmacology, Schizophrenia Patient Outcome Research Team (PORT), American Psychiatric Association (APA), Indian Psychiatric Society (IPS), and World Federation of Association of Biological Psychiatry (WFSBP).
The salient factors regarding the use of anticholinergics with antipsychotics are highlighted [Table 2].
Table 2: Salient factors from guidelines regarding use of anticholinergics with antipsychotics
CONCLUSION
There exists no scientific rationale for preemptively prescribing anticholinergics with antipsychotics. Despite existing evidence-based guidelines advocating against prophylactic use of anticholinergics with antipsychotics, such use remains rampant. Many patients remain on these medications over long periods, which is not rational. This nonjudicious use has implications in terms of increased central and peripheral anticholinergic side effects, possible worsening of extrapyramidal symptoms and nonadherence with medications. There is a need for the clinicians to guard against the tendency to add anticholinergics as a routine. A considered decision to start anticholinergics should be taken for emergent EPS which respond to such medication and for the shortest duration possible. We strongly recommend against preemptive adding of anticholinergic medications, while prescribing SGAs.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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