Antipsychotics Their Mechanisms of Action and Serious Reactions

Schizophrenia DSM-IV-TR abbreviated criteria  2 or more of these for most of 1 month: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms  Social/occupational dysfunction  Duration of at least 6 months  R/o Schizoaffective and Mood disorders  R/o substance use & general med condition “Schizophrenia cannot be understood without understanding despair.” R.D. (Ronald David) Laing (1927–1989), British psychiatrist. The Divided Self, ch. 2 (1959).

Schizophrenia DSM-IV-TR abbreviated criteria cont.  In the presence of pervasive developmental disorders, must have prominent delusions or hallucinations “Hallucinations and delusions [are] both symptoms [that] reflect a ‘loss of ego boundaries’: the patient is unable to distinguish between his or her own thoughts and perceptions and those that he or she obtains by observing the external world.” 2 “The psychopathology of schizophrenia is one of the most intriguing, since it permits a many- sided insight into the workings of the diseased as well as the healthy psyche.” Eugen Bleuler

Antipsychotics “Though the disease is not cured by drug therapy, the symptoms of schizophrenia, including thought disorder, emotional withdrawal, and hallucinations or delusions, may be attenuated by antipsychotic drugs. Unfortunately, protracted therapy (years) is often needed and can result in sever toxicity in some patients.” 1 “Just remember that you have to worry when the lights talk back.” Mara Sommer

Antipsychotic Classes Phenothiazones, thioxanthenes, and butyrophenones, oh my! “I don’t do drugs. I am drugs.” Salvidor Dali 1

Antipsychotic Classes Atypically  Heterocyclics (more effective and less toxic in some cases) Clozapine [Clozaril] Onlanzapine [Zyprexa] Risperidone [Risperdal] Quetiapine [Seroquel] Ziprasidone [Geodon] Etc. “…in my grading, and he tried to make other people like they were good enough to be in Hollywood or something, you know I’s be the last one down the ladder.” 2 Andreasen, The Broken Brain, p. 61

Mechanism of Action Dopamine hypothesis  Excess of dopamine in specific neural tracts D 2 receptor is in the caudate putamen, nucleus accumbens, cerebral cortex, and hypothalamus  Many antipsychotics block the D 2 receptor  Dopamine agonists exacerbate schizophrenia  Increased density of dopamine receptors in the brains of untreated schizophrenics “Reality is a crutch for people who can’t cope with drugs.” Lily Tomlin

Mechanism of Action Dopamine pathways  Mentation & Mood Mesocortical Mesolimbic  Extrapyramidal Function Nigrostriatal  Prolactin release Tuberoinfundibular  Emesis Chemoreceptor trigger zone “The seat of the soul and the control of voluntary movement - in fact, of nervous functions in general, - are to be sought in the heart. The brain is an organ of minor importance.” Aristotle (from De motu animalium, 4th century B.C.) 3 3

Mechanism of Action Other receptors  Clozaril has low D 2 affinity but significant D 4 and 5-HT 2 (serotonin) receptor blocking actions  Most atypicals have high 5-HT 2A affinity and may also interact with D 2 and other receptors “Sports make you grunt and smell. Stay in school, use your brains. Be a thinker, not a stinker. ” Apollo Creed (character played by Carl Weathers in the movie Rocky, 1976) 2

Desirable Effects Reduction of positive symptoms  Hyperactivity, bizarre ideation, hallucinations, delusions  Typicals and atypicals reduce positive symptoms Improve negative symptoms  Emotional blunting, social withdrawal  Atypicals Also reduces psychotic symptoms in schizoaffective disorder, Tourette’s syndrome, toxic psychoses Except thioridazine phenothiazines have antiemetic properties via H 1 blocking “Better brains in the head than riches and confusion.” Greek proverb

Adverse Effects Reversible parkinsonism, akathisias, and dystonias  Treatment is to decrease antipsychotic dose or use muscarinic blocking agents  Less common with atypicals Tardive dyskinesias  Develop within 6 months to several years of therapy  Antimuscarinics increase TD severity  May be caused by dopamine receptor sensitization because increasing antipsychotic doses temporarily attenuates symptoms  May be irreversible  No pharmacological treatment “You've probably read in People that I'm a nice guy - but when the doctor first told me I had Parkinson's, I wanted to kill him.” Michael J Fox

Adverse Effects Autonomic effects (tolerance may develop with continued therapy)  Muscarinic blockade – dry mouth, constipation, urinary retention, visual problems  Alpha adrenergic receptor blockade – postural hypotension, failure to ejaculate Endocrine and metabolic effects  Hyperprolactinemia, amenorrhea, galactorrhea, infertility, weight gain, gynecomastia Neuroleptic Malignant Syndrome  Muscle rigidity, impairment of sweating, hyperpyrexia, autonomic instability  May be life threatening  Treat with dantrolene and possibly dopamine agonists “I will not give a fatal draught to anyone if I am asked, nor will I suggest any such thing.” Hippocrates, Hippocratic Oath (Hippocratic Writings, Penguin Classics, 1983)

Adverse Effects Sedation  More marked with phenothiazines  Except for sertindole, all atypicals block histamine receptors Miscellaneous toxicities  Thioridazine – retinal deposits causing visual impairments, high doses leads to fatal ventricular arrhythmias  Sertindole – prolonged QT segment leading to arrhythmias  Clozapine – 1-2% incidence of agranulocytosis, seizures at high doses Overdose toxicity  Other than thioridazine (cardiotoxicity), overdoses are usually not fatal  Lowers seizure threshold  Hypotension responds to fluid replacement “A collection of a hundred great brains makes one big fathead.” Carl Gustav Jung

References 1. Trevor A. J., et al. (2002). Katzung & Trevor’s Pharmacology: Examination & Board Review. New York: Lange Medical Books/McGraw-Hill 2. Andreasen, N. C., & Black, D. W. (2001). Introductory Textbook of Psychiatry. Washington DC: American Psychiatric Publishing, Inc. 3. Blumenfeld, H. (2002). Neuroanatomy through Clinical Cases. Sunderland, MA: Sinauer Associates, Inc. “Insane in the membrane, Insane in the brain!” Cypress Hill 1993