ANTIPSYCHOTIC DRUGS

1. ANTIPSYCHOTIC DRUGS Martin Štěrba, PharmD., PhD. Associate professor 2012

2. Psychotic disorders (psychosis): • are severe mental disorders that cause abnormal thinking and perceptions. • Classification of psychotic disorders • Schizophrenia– see below • Schizoaffective disorder– disorder of both thought and mood • Delusional disorder– incl. paranoid psychosis • Substance-induced psychotic disorder– use/withdrawal of amphetamines, cocaine, alcohol, LSD, psilocybe… • Psychotic disorder due to a medical condition(organic psychosis) - disturbances caused by head injury or tumor • others

3. Schizophrenia • Definition: • Chronic (relapsing and remitting) disorder of though • characterised by acute psychotic episodes • periods of impaired psychosocial functionality and residual symptoms in between • Typical feature – is a loss of touch with reality • Life-time prevalence– 1% of population • Onset in adolescence/early adulthood • Etiology – unclear • significant genetic component • neurodevelopmental theory – aberrant intrauterine brain development (infections, hypoxia?)  abnormal neuronal shape, position and connections • Highly disabling – strong medical, social and economical implications

4. Schizophrenia-Pathophysiology • Morphological changes • brain asymmetry with decreased cortical/hyppocampal size and increased ventricular size • Neurotransmitter changes • theories were derived from pharmacological observations • unfortunately nodetail understanding to the neurochemistry • Dopamine theory– central and most important one, it will be discussed further in detail • Glutamate theory • Psychotic-like symptoms induced by administrations of NMDA-antagonists (ketamine and phencyclidine • Reduction of glutamatergic and increased dopaminergic neurotransmission • → impairment of gating fucntion of GABA neurons • Serotonin theory • schizophrenia-like symptoms induced by LSD,psilocybine • many atypical antipsychotics block also 5-HT receptors (! 5-HT2A)

5. Dopamine theory:dopaminergic systems in CNS

6. Dopamine theory of schizophrenia • Symptoms of schizophrenia - hyperactivity of dopaminergic pathways in mesolimbic/mesocortical system • Psychotic symptoms and related behavioural changes can be • Induced by • Drugs causing dopamine release – e.g., amphetamines • D-agonists (e.g., bromocryptine) and dopamine precursors (like L-DOPA) • Inhibited by • Drugs blocking dopamine storage (e.g., reserpine) • D-antagonists • Dopamine receptors – D1 type(D1 and D5) and D2-type (D2, D3, D4) • D2-receptors • Are evidently involved • correlation between D2-antagonistic effects and antipsychotic action • Clinical response in occupancy of 60-80% of D2 receptors • for atypical drugs 30-50% is enough • Some theories suggest • overactivation of D2 receptors in subcortical regions (positive symptoms) • Deficient activation of D1 receptors (negative symptoms)

7. Symptom clusters In schizophrenia • Positive symptoms • Delusions(fixed false beliefs, often paranoid/conspirative in nature) • Hallucinations(usually hearing of voices, typically spurring) • Incoherent thought(disconnection - loosing of associations, inability of logical analysis of the situation, ambivalence – contradictory thoughts) • Suspiciousness, hostility and potentially aggression • Disorganized speech • Stereotype/abnormal movements • Negative symptoms • Affective flattening– poor emotional experience • Anhedonia– loss of the capacity to experience pleasure • Avolition- lack of desire, drive, or motivation to pursue goals • Withdrawal from social contacts • Cognitive symptomes • Impaired attention, working memory and executive function • Clinical picture may vary considerably, especially according to the positive/negative symptoms balance

8. Goals and means of treatment • Goals • To suppress any acute psychotic episode • To prevent relapses and progression of the disease • To restore/keep the psychosocial functionality (family, job and social networks) • Therapy • should be complex • is not causal • Pharmacologic– the mainstay of the treatment • Common mechanism of action: D2-antagonism • Additional mechanisms: antagonism on 5-HT2A/C.α1, M, H1, • Adverse effects • Therapeutic effects

9. Pharmacotherapy of Schisophreniageneral aspects • Response in 70% of patients • 30% are treatment resistant forms = big clinical issue!!! • Negative symptomsrespond much less than positive symptoms • improved in atypical drugs • The full antipsychotic effect deserve weeks (3-4 weeks). • only non-specific sedative and aggression controlling effects can be induced immediately • Monotherapy is preferable • combinations only in resistant forms

10. Pharmacotherapy of Schisophreniageneral aspects • Long-term treatment • is usually initiated with newer atypical drugs • Compliance– often big issue, i.m. injection (acute episode) or „depot“ i.m. forms (to avoid chronic non-compliance) • Dose is usually gradually titrated, adverse effects should be closely monitored • Typical antipsychotics • useful in acute psychotic episode with strong aggression (sedative effects, injectable forms are available)

11. Pharmacokinetics of antipsychotics • Route ofadministration • oral or by i.m. injection • once or twice a day. • Generally highly lipophilic drugs • highly bound on plasma proteins • large distribution into the tissues (high Vd), risk of accumulation • T1/2 of most antipsychotics • is long (15-30 hours) • CL depends entirely on hepaticbiotransformation • mostly CYP 450-dependent (exception ziprasidone) • genetic polymorphisms (e.g., in CYP 2D6 - substrates risperidon) • Slow- release („depot“) preparations • flupentixoldecanoat, fluphenazinedecanoat • active drug is esterified with heptanoic or decanoic acid • dissolved in oil. • Given as an i.m. inj., the drug acts for 2-4 weeks.

12. Classification of antipsychotic drugs: I. typical antipsychotics a) basal (sedative): -chlorpromazine(typical example, a phenothiazine structure) - chlorprotixene,thioridazine b) incisive: -haloperidol(typical example, a butyrophenone structure) - fluphenazine, flupenthixol, clopenthixol II. atypical antipsychotics: a) Multi Acting Receptor Targeted Antipsychotics (MARTA) -olanzapine, zotepin, quetiapine, clozapine D1/2, 5-HT2A,α, H1, M and receptor antagonists b) Dopamine and serotonin receptor antagonists -risperidone, ziprasidone, aripiprazole c) D2-selective antagonists -sulpiride, amisulpiride

13. Classificationofantipsychotics • Incisive vs. sedative (typical) antipsychotics • Incisive - more potent and selective D2-antagonits than sedative (basal) drugs • Incisive drugs are more effective however, they induce significant problems with extrapyramidal adverse effects • Sedative drugs are weaker D2-antagonists,but block also H1,α1, M (which explain sedative effects as well as some adverse effects) • Atypical vs. typical antipsychotics • Atypical drugs • less extrapyramidal complications • Have improved efficacy against negative symptoms • Might be useful in treatment-resistant groupof patients (especially clozapine) • Difference in overal efficacy ?

14. Adverse effects - A- type(dose dependent) I. Extrapyramidal motor disturbances - result from D2 blockade in the nigrostriatal pathways - more frequent in typical (especially incisive) antipsychotics • Acute (reversible) • Parkinson-like symptoms(further details on next seminar) • Tremor • Rigidity • Bradykinesia/akinesia: • Acute dystonias • - severemuscle spasms, very painful (occur within initial 24-96h) • Orofacialmuscles(e.g., blepharospasm - eye lid spasm, oculogyric crisis – turning of eye bulbi upward), • Neck muscle spasms (torticollis – „wry neck“) • Tongue protrusion Can be life-threatening – pharyngeal-laryngeal forms • Akathasia • motor restlessness (restless leg syndrome) • „inner restlessness“ • Treatment: benzodiazepines, beta-blockers

15. Adverse effects - A- type(dose dependent) I. Extrapyramidal motor disturbances • Slowly developing (often irreversible) • Tardive dyskinesia • involuntary movements in face/tongue and limbs appearing after months or years of antipsychotic treatment. • Includes: tongue thrusting, rolling and „fly catching“, • Chewing and „rabbit lip syndrome“ (impaired speech, eating) • Grimassing, blinking… + choreiform movements of extremities (caused by up-regulation of D-receptors in striatum?)

16. Mechanisms of EPS Dopamine (-) cholinergic pathway (+) S. NIGRA CORPUS STRIATUM GABA (-)

17. Adverse effects – A -type II. Decreased seizure threshold - in predisposed persons may induce seizures (convulsions)!!! - mainly in high doses III. Sedation and cognitive deficit - occurs with many antipsychotics - antihistamine (H1) activity significantly contributes to this effects (especially sedative typical drugs but also others) IV. Antimuscarinic activity - blurring of vision - increased intraocular pressure (glaucoma!) - dry mouth and eyes - constipation - urinary retention

18. Adverse effects – A -type V. Cardiovascular adverse reactions - Orthostatic hypotension - α-adrenoreceptorsblockade - Drug induced QT syndrome (e.g., thioridazine) VI. Weight gain + dyslipidemia - probably related to 5-HT blockade and apetite stimulation VII. Diabetes - atypical, esp. olanzapine and clozapine

19. Adverse effects B –typeunpredictable • - neuroleptic malignant syndrome • Muscle rigidity, rapid rise in body temp. and mental confusion, • instable blood pressure and tachycardia. • Death rate 10-20%(renal or cardiovascular failure) • Discontinuation of therapy • Supportive care is essential (cooling!). • It is more frequent with typical antipsychotics. • - jaundice(with older drugs, mainly phenothiazines) • Usually mild cholestatic hepatitis (obstructive origin), disappears quickly • when the drug is stopped • - leukopenia and agranulocytosis • rare but potentially fatal complication occurring in clozapine – its use requires • regular monitoring of blood cell counts

20. Adverse effects Others -urticarial skin reactions • mainly phenothiazines - depositions - in skin in complex with melanine gray discolorations of skin and excessive UV light sensitivity - in cornea/lens(vision disturbances)

21. Selectedtypicaldrugs • Chlorpromazine • 1st classic neuroleptic drug, inexpensive • Strong autonomic effects (blocks also ,M, H1) • Route: p.o., i.m., i.v. • Ind.: • schizophrenia (against positive symptoms) • Bipolar disorder (against mania) • Not to be used: in patients with dementia, treated by IMAO • Slow discontinuation after longer treatment • Be careful about combination with: sedative drugs, QT-prolonging drugs, hypotensives • Haloperidol • Prototype incisive neuroleptic drug • Butyrophenone (not phenothiazine) • Ind.: • Schizophrenia (both acute and chronic) • Korsakov syndrome (in alcoholics – acute amnesia, confusion, delusions, apathy) • Delusional disorders (like paranoid disorders) • Psychomotoriccalm-down • Antiemetics • Lessvegetativesymptoms, more extrapyramidalsymptoms

22. Selectedatypicaldrugs • Olanzapine • MARTA – much less antiD2 and more anti5-HT2A • IND • Schizophrenia • Manic phase of bipolar disorder (acute treatment and prophylaxis) • Superior to haloperidol in overall efficacy in schizophrenia • Good response of positive and negative symptoms • Response in partial resistance and failure of other atypical drug • Adverse reactions: body weight gain, dyslipidemia, diabetes (monitoring!), slight sedation…minimal problems with EPS • Clozapine • Developed in 70s, but not introduced into clinical practice • Adverse effect: leukopenia and agranulocytosis (monitoring), epileptic seizures, anticholinergic effects, • The only drug clearly effective in pharmacoresistant forms of disease!!! • Very good response in negative symptoms • Drug of 3rd choice due to the safety concerns