psychopharmacs : antipsychotics

Psychopharmacs : antipsychotics

prof. MUDr. Eva Češková, CSc.prof. MUDr. Eva Češková, CSc.

Dept. of Psychiatry, Dept. of Psychiatry,

Masaryk University , BrnoMasaryk University , Brno

Psychopharmacs : antipsychotics

definition and historyclassification according to chemistry classification according to clinical efficacymechanism of actionpharmacokineticdoses 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 chemistryphenothiazines - 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 ringbutyrophenones (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 treatmentaffective 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 H1 M

SulpirideAmisulpiride

++(+)

Ziprasidone + + +

Risperidone + + + <+

Quetiapine + + + +

Zotepine + + + + <+

Olanzapine + + + + +

Clozapine + + + + +

Depot antipsychotics

Benefits of depot (long-acting) injections:optimise treatment adherence (reduce relapse)assure delivery, avoid first-pass metabolismuse lowest effective dose, predictable plasma levels simple administration, regular contact with team Available depot APs: fluphenazine decanoate/enanthate flupenthixol decanoate, haloperidol decanoatezuclopenthixol 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 actionAll the known APs share the common property of

blocking DA receptor:blockade of DA receptors in the nigrostriatal DA

pathway - a drug-induced parkinsonismblockade 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)

180120 – 180140 – 18080 – 160100 – 160 Ziprasidone

3015 – 2015 – 3010 – 2010 – 20 Aripiprazole

950400 – 750500 – 800300 – 600350 – 700 Quetiapine

4012.5 – 22.515 – 2510 – 2010 – 20 Olanzapine

850300 – 550400 – 600250 – 500300 – 500 Clozapine

Atypicals

Maintenance treat.

(mg/day)

Acute treat.

(mg/day)

Maintenance treat.

(mg/day)

Acute treat.

(mg/day)

Highest final acute dose

(mg/day)

Multi-episode patientFirst-episode patient

Medication

10.53.5 – 5.54 – 6.52 – 4.52.5 – 5 Risperidone

115Partial response to treatment

63Little or no response to treatment

Maximum number of weeks to wait

Minimum number of weeks to wait

Duration of treatment

104Partial response to treatment

63Little or no response to treatment

Maximum number of weeks to wait

Minimum number of weeks to wait

Inadequate response to initial antipsychotic

Inadequate response to second antipsychotic

Side effects

Acute extrapyramidal side effects:parkinsonian syndromeacute dystoniaakathisia

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 hypotensioncardiac rhythm disturbances

Dermatological and ocular effects

Endocrine effects

Hepatic effects

Haematological effects

Side effects

Metabolic side effects:hyperprolactinemiaweight gaindiabetesdyslipidemia

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 ofantipsychotic weight gain (10 weeks)

Mea

n c

han

ge

in b

od

y w

eig

ht

(kg

)

(Allison DB et al. Am J Psychiatry 1999;156:1686–96)

5

4

3

2

1

0

–1

Place

bo

Molin

done

Zipra

sidone

Fluphen

azin

e

Haloper

idol

Non-phar

m c

ontrol

Risper

idone

Chlorp

rom

azin

e

Sertin

dole

Thiorid

azin

e

Olanza

pine

Cloza

pine

Hierarchy of weight gain but also differential rate (trajectory) and total gain (plateau)

drug Weightgain

Risk fordiabetes

Worseninglipidprofile

Clozapine +++ + +

Olanzapine +++ + +

Risperidone ++ D D

Quetiapine ++ D D

Aripiprazol +/- - -

Ziprasidon +/- - -

D discrepant results Diabetes Care, 27, 2004, 2, 596-601

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).

-5

0

5

10

15

20

25

30

35

40

Zipr.160 mg

Risp.16 mg

Olan.20 mg

Seroq.750 mg

Thior.300 mg

Halo.15 mg

(n=24) (n=25) (n=27) (n=27) (n=31) (n=30)

Adverse effects - QTc prolongation

Mean changeof QTc(msec)

Pfizer Study 54

Indications

schizophrenia disorderdelusional disordermood disorders with psychotic symptomspsychosis 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