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  1. Psychopharmacs : antipsychotics prof. MUDr. Eva Češková, CSc. Dept. of Psychiatry, Masaryk University , Brno

  2. Psychopharmacs : antipsychotics • definition and history • classification according to chemistry • classification according to clinical efficacy • mechanism of action • pharmacokinetic • doses and duration of treatment • side effects • indication • literature

  3. Definition, history Neuroleptics ( antipsychotics, AP ) are psychopharmacs influencing psychic integration in a positive way Antipsychotics are the cornerstone of treatment of schizophrenia. The first antipsychotic drugs was discovered by accident in the 1950s when a drug thought to be an antihistamine (chlorpromazine) was serendipitously observe to have unique antipsychotic effect

  4. Classification according to chemistry • phenothiazines - 3 ring nucleus, drugs differ in the side chains(aliphatics, piperidines, piperazines) • thioxanthenes - differ from the phenothiazine by the substitution of a C instead of N in the middle ring • butyrophenones (haloperidol) • dephenylbutyrylpiperidines (penfluridol, pimozid) • dibenzodiazepines (clozapine) • benzisoxale (risperidone) • thienobenzodiazepine (olanzapine) • dibenzothiazepine (quetipine) • benzamide • others

  5. Classification according to the clinical efficacy Conventional antipsychotics: • incizive (high potency):e.g., haloperidol, fluphenazine, perphenazine, trifluoperazine) • basale (low potency):e.g., chlorpromazine , thioridazine Atypical antipsychotics: aripiprazole, clozapine, olanzapine, risperidone , quetiapine , ziprasidone, zotepine

  6. Conventional antipsychotics Limitations of conventional antipsychotics: • insufficient efficacy with targeted symptoms (e.g., negative symptoms, cognitive deficits) • positive symptoms resistant to therapy in (15–48% of patients) • motor side effects (irreversible tardive dyskinesia in 5–10% of patients with long-term treatment • affective side effects (dysphoria, anhedonia) • poor adherence (only 30% of patients during long-term treatment)

  7. Classification of atypical antipsychotics • specific D2 and D3 antagonists -sulpiride, amisulpiride (f.o. Solian) • serotonin/dopamine antagonists SDA - risperidone (f.o.Risperdal), ziprasidone (f.o. Abifal) • multireceptor targeted antagonists (MARTA) clozapine (f.o. Leponex), olanzapine (f.o.Zyprexa), quetiapine (f.o. Seroquel), zotepine (f.o. Zoleptil)

  8. Atypical antipsychotics (new APs, 2nd generation APs ) Advantages of atypical antipsychotics Better efficacy: in treatment-resistant patients +(+) in negative symptoms ++ in neuropsychological deficits ++ no clinically relevant motor side effects +++ Fewer affective side effects +(+) Better adherence ++ Better subjective well-being and quality of life ++

  9. Classification of atypical antipsychotics - receptor binding affinities

  10. Depot antipsychotics Benefits of depot (long-acting) injections: • optimise treatment adherence (reduce relapse) • assure delivery, avoid first-pass metabolism • use lowest effective dose, predictable plasma levels • simple administration, regular contact with team Available depot APs: • fluphenazine decanoate/enanthate • flupenthixol decanoate, haloperidol decanoate • zuclopenthixol decanoate, oxyprothepin decanoate • available depot atypical APs -Risperdal Consta

  11. relapse rates are lower with continuous antipsychotic therapy ! • relapses with APs signif. lower than with placebo (circa 20% vs 50%) • poor adherence leads to relapse and high costs to individuals, families, carers and society • stopping medication is the most powerful predictor of relapse

  12. Mechanism of action • all available clinically effective APs block D (dopamine) receptors, the potency to reduce psychotic symptoms is most closely correlated with the affinity to D2 receptor • others systems may play important role (glutamate, noradrenaline, serotonin, GABA, neuropeptides) • atypical APs differentially affect other systems (serotonin) - more specific pharmacological action generally safer, better tolerated • APs differ in their ability to block the various receptors - e.g. in their side effects profiles, but no in their therapeutic profiles

  13. Mechanisms of action All the known APs share the common property of blocking DA receptor: • blockade of DA receptors in the nigrostriatal DA pathway - a drug-induced parkinsonism • blockade of DA receptors in the mesolimbic DA pathway - antipsychotic efficacy (especially positive symptoms) • blockade of DA receptors in the mesocortical DA pathway - blunting of emotions and cognitive side effects • blockade of DA receptor in tuberoinfundibular DA pathway - elevation of prolactin levels

  14. Mechanism of action - dopaminergic pathways of the CNS Stahl SM.: Essential Psychopharmacology, 2000

  15. Pharmacokinetics • most APs have high binding to plasma protein, volume of distribution, and lipid solubility • the most important clinical generalisation is that all the APs can be given in a one daily dose once patient is in a stable condition • APs are metabolised in the liver and reach steady plasma levels in 5-10 days.

  16. Medication First-episode patient Multi-episode patient Highest final acute dose (mg/day) Acute treat. (mg/day) Maintenance treat. (mg/day) Acute treat. (mg/day) Maintenance treat. (mg/day) Atypicals Risperidone 2.5 – 5 2 – 4.5 4 – 6.5 3.5 – 5.5 10.5 Clozapine 300 – 500 250 – 500 400 – 600 300 – 550 850 Olanzapine 10 – 20 10 – 20 15 – 25 12.5 – 22.5 40 Quetiapine 350 – 700 300 – 600 500 – 800 400 – 750 950 Aripiprazole 10 – 20 10 – 20 15 – 30 15 – 20 30 Ziprasidone 100 – 160 80 – 160 140 – 180 120 – 180 180 Doses (and dose equivalence of atypicals)

  17. Minimum number of weeks to wait Maximum number of weeks to wait Little or no response to treatment 3 6 Partial response to treatment 4 10 Minimum number of weeks to wait Maximum number of weeks to wait Little or no response to treatment 3 6 Partial response to treatment 5 11 Duration of treatment Inadequate response to initial antipsychotic Inadequate response to second antipsychotic

  18. Side effects Acute extrapyramidal side effects: • parkinsonian syndrome • acute dystonia • akathisia Tardive dyskinesia (new antipsychotics 0.6% vs haloperidol 5.3%) Neuroleptic malignant syndrome (NMS)

  19. Side effects Autonomic side effects: • anticholinergic (blurred vision, dry mouth, constipation, urine retention) • hypersalivation Cardiovascular effects: • orthostatic hypotension • cardiac rhythm disturbances Dermatological and ocular effects Endocrine effects Hepatic effects Haematological effects

  20. Side effects Metabolic side effects: • hyperprolactinemia • weight gain • diabetes • dyslipidemia QTc prolongation

  21. Hyperprolactinemia Prolactin (PRL): Pituitary hormone involved in lactation, learning, body temperature, immune response, cortisole secretion • normal values: 5 - 25 ng/ml (or U/l) in men and non-pregnant and non-lactating women • prolactin-related side effect: galactorrhoea, amenorrhea, sexual dysfunction • PRL is elevated by: D2 blockers (antipsychotics) sleep, stress, exercise, sexual activity, food, pituitary lesions, seizure disorder, renal/hepatic disease, hypothyroidism

  22. Side effects - hierarchy ofantipsychotic weight gain (10 weeks) 5 4 3 2 1 0 –1 Mean change in body weight (kg) Placebo Clozapine Sertindole Molindone Olanzapine Haloperidol Ziprasidone Risperidone Thioridazine Fluphenazine Chlorpromazine Non-pharm control Hierarchy of weight gain but also differential rate (trajectory) and total gain (plateau) (Allison DB et al. Am J Psychiatry 1999;156:1686–96)

  23. Consensus development conference on antipsychotic drugs and obesity and diabetes (American diabetes association, APA, American Association of clinical endocrinologists, North American Association for the study of obesity).

  24. Adverse effects - QTc prolongation Mean change of QTc(msec) 40 35 30 25 20 15 10 5 0 Olan.20 mg Halo.15 mg Zipr.160 mg Risp.16 mg Seroq.750 mg Thior.300 mg -5 (n=24) (n=25) (n=27) (n=27) (n=31) (n=30) Pfizer Study 54

  25. Indications • schizophrenia disorder • delusional disorder • mood disorders with psychotic symptoms • psychosis secondary to nonpsychiatric medical condition or substance-induced condition

  26. References : • Allison DB, Mentore JL, Moonseong H.: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry, 156, 1999, pp. 1686-1696 • Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 27, 2004, 2, pp. 596-601 • Janicak PG.: Handbook of psychopharmacology, Baltimore: Williams and Willkins, 1999 • Kaplan HI, Sadock BJ, Grebb JA.: Kaplan and Sadock´s synopsis of psychiatry, Baltimore : Williams and Wilkins, 1997 • Stahl, SM.: Psychopharmacology of antipsychotics, London: Martin Dunitz, 1999 • Stahl SM.: Essential Psychopharmacology, Cambridge: Cambridge University Press,2000