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. 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

17. 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

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: 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 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)

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).

25. 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

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

27. References :
Allison DB, Mentore JL, Moonseong H.: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry, 156, 1999, pp
Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care, 27, 2004, 2, pp
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