Medical Pharmacology Chapter 16:  Pharmacology of Antipsychotics Drugs

• First Generation Antipsychotic Medications

  • Adverse Effects

   

  • Adverse Effects

    • The adverse effect profile of First Generation Antipsychotics (FGAs) is well characterized and derives directly from their pharmacology.

      • While the specific pattern differs between agents based on receptor binding selectivity and potency, the following categories represent the most clinically significant concerns.

    • Extrapyramidal Symptoms (EPS)

      • Extrapyramidal symptoms are the most common and limiting neurological adverse effects of FGAs, arising from D₂ blockade in the nigrostriatal pathway.

        • The symptoms are monitored using validated rating instruments such as the Simpson-Angus Scale (SAS), which was published in 1970 and remains the standard clinical tool for assessing drug-induced parkinsonism.¹²

          • Janno S Holi M Tuisku K Wahlbeck Validity of Simpson-Angus Scale (SAS) in a naturalistic schizophrenia population B.MC Neurol. 2005 March 17;5:5. https://pmc.ncbi.nlm.nih.gov/articles/PMC555761/

        • Four principal EPS syndromes are recognized:

          • Acute Dystonia

            • Acute dystonia consists of sustained, involuntary muscle contractions producing abnormal postures or movements.

              • This presentation typically occurs within hours to days of initiating high-potency FGAs.

                • Clinically significant presentations include oculogyric crisis (sustained upward deviation of the eyes), torticollis (neck hyperextension), opisthotonos (full-body arching), and laryngeal dystonia (potentially life-threatening stridor).

                • Risk is highest in young men and in those receiving highpotency agents. Akisthisia

                  • Treatment is immediate: intramuscular diphenhydramine or benztropine produces rapid resolution.

            • "Diagnosis and Management of Acute Dystonia Reactions"

              Attribution: Jibson M Diagnosis and Management of Acute Dystonia Reactions. Psychopharmacology Institute.April 17, 2018. https://www.youtube.com/watch?v=r2mfdyGFHbY Psychopharmacology Institute https://www.youtube.com/@Psychopharmacologyinstitute

          • Akisthisia

            • Akathisia is a subjective state of motor restlessness and an inability to remain still, often described by patients as a compelling urge to move.

              • Akathisia is among the most distressing EPS subtypes and is frequently misidentified as agitation or worsening psychosis, a critical diagnostic error, as increasing the antipsychotic dose will worsen rather than resolve akathisia.

                • Management strategies include dose reduction, switching to a lower-potency agent, or adding propranolol or a benzodiazepine.

            • What is Akisthisia

              Attribution Witt-Doerring J What is Akathisia?-The worst side effect of any psychiatric medication. https://www.youtube.com/watch?v=oBJZHSLa03o December 14, 2022. Taper Clinic https://taperclinic.com/about-us/

          • Drug-Induced Parkinsonism

            • Drug-induced parkinsonism (DIP) mimics idiopathic Parkinson's disease with the classic triad of resting tremor, cogwheel rigidity, and bradykinesia.

              •  The side effect typically develops within weeks of FGA initiation, is dose-dependent, and is more common in elderly patients.

                • Management includes dose reduction, switching agents, or adding an anticholinergic agent (benztropine, trihexyphenidyl).

                  • Prophylactic anticholinergic use is controversial and generally reserved for high-risk patients.

    
    

  References

  Delay J, Deniker P. Le traitement des psychoses par une méthode neurolytique dérivée de l'hibernothérapie. CR Congr Méd Alién Neurol (France). 1952;50:497–502. [No PubMed entry — historical conference proceeding] Carlsson A, Lindqvist M. Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol (Copenh). 1963;20:140–144. Click for article. Creese I, Burt DR, Snyder SH. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science. 1976;192(4238):481–483.  Click for article. Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature. 1976;261(5562):717–719.  Click for article. NIMH Psychopharmacology Service Center Collaborative Study Group. Phenothiazine treatment in acute schizophrenia. Arch Gen Psychiatry. 1964;10(3):246–261.  Click for article. Davis JM. Overview: maintenance therapy in psychiatry. I. Schizophrenia. Am J Psychiatry. 1975;132(12):1237–1245.  Click for article. Lieberman JA, Stroup TS, McEvoy JP, et al.; CATIE Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–1223.  Click for article Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 2012;379(9831):2063–2071. Click for article. Schooler NR, Kane JM. Research diagnoses for tardive dyskinesia. Arch Gen Psychiatry. 1982;39(4):486–487.  Click for article (additonal information) Kane JM, Woerner M, Lieberman J. Tardive dyskinesia: prevalence, incidence, and risk factors. J Clin Psychopharmacol. 1988;8(4 Suppl):52S–56S.  Click for article. Caroff SN, Mann SC. Neuroleptic malignant syndrome. Med Clin North Am. 1993;77(1):185–202.  Click for article Simpson GM, Angus JWS. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl. 1970;212:11–19. Click for article American Psychiatric Association Practice Guideline Writing Group (Keepers GA, Chair). The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia [executive summary]. Am J Psychiatry. 2020;177(9):868–872 [full guideline: Washington DC: APA, 2021]. Click for article Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 2009;373(9657):31–41.  Click for article Glazer WM, Kane JM. Depot neuroleptic therapy: an underutilized treatment option. J Clin Psychiatry. 1992;53(12):426–433.  Click for article

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