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Psychopharmacs :
antipsychotics
prof. MUDr. Eva Češková, CSc.
Dept. of Psychiatry,
Masaryk University , Brno
Psychopharmacs : antipsychotics
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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
Drug
D2
5HT2
Alfa 1
+
+(+)
+
+
+
Risperidone
+
+
+
<+
Quetiapine
+
+
+
+
Zotepine
+
+
+
+
<+
Olanzapine
+
+
+
+
+
Clozapine
+
+
+
+
+
Sulpiride
Amisulpiride
Ziprasidone
H1
M
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)
First-episode patient
Multi-episode patient
Acute treat.
(mg/day)
Maintenance treat.
(mg/day)
Acute treat.
(mg/day)
Maintenance treat.
(mg/day)
Highest final
acute dose
(mg/day)
2.5 – 5
2 – 4.5
4 – 6.5
3.5 – 5.5
10.5
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
Medication
Atypicals
Risperidone
Clozapine
Duration of treatment
Inadequate response to initial antipsychotic
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
Inadequate response to second antipsychotic
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
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)
Mean change in body
weight (kg)
5
4
3
2
1
0
–1
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).
drug
Weight
gain
Risk for
diabetes
Clozapine
+++
+
Worsening
lipid
profile
+
Olanzapine
+++
+
+
Risperidone ++
D
D
Quetiapine
D
D
Aripiprazol +/-
-
-
Ziprasidon
-
-
++
+/-
D discrepant results
Diabetes Care, 27, 2004, 2, 596-601
Adverse effects - QTc prolongation
Mean
change
of QTc
(msec)
40
35
30
25
20
15
10
5
0
-5
Pfizer Study 54
Olan.
20 mg
Risp.
16 mg
(n=24)
(n=25)
Seroq. Halo.
750 mg 15 mg
(n=27)
(n=27)
Zipr.
160 mg
Thior.
300 mg
(n=31)
(n=30)
Indications
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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