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

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

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

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

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

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)

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)

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 ++

Classification of atypical antipsychotics - receptor binding affinities

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

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

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

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

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

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.

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

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

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)

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

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

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

Side effects - hierarchy of antipsychotic weight gain (10 weeks) 5 4 3 2 1 –1 Mean change in body weight (kg) Placebo Molindone Ziprasidone Haloperidol Sertindole Risperidone Thioridazine Olanzapine Clozapine 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)

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).

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

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

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