ANTIPSYCHOTIC DRUGS

1. ANTIPSYCHOTIC DRUGS Martin Štěrba, PharmD., PhD. 2008

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… • 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 characterized by acute psychotic episodes bridged by periods showing impaired psychosocial functionality and residual symptoms • Typical feature – is a loss of touch with reality • Life-time prevalence – 1% of population • Onset in adolescence/early adulthood • Ethiology – 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/hippocampal size and increased ventricular size • Neurotransmitter changes The theories were largely derived from observations of pharmacological observations, unfortunately not on detail understanding to the neurochemistry of particular neutronasmitter system • Dopamine theory– central and most important one, it will be discussed further in detail • Glutamate theory – comes from psychotic symptoms induced by administrations of NMDA-antagonists (ketamine and phencyclidine), together with observations from post-mortem examination • It was proposed that reduced glutamatergic and increased dopaminergic neurotransmissions may impair the gating function of GABA-ergic neurons projecting themselves into the thalamus – which cause deteriorations of the SENSORY „GATE“. • Serotonine theory – schizophrenia-like symptoms induced by LSD, many atypical antipsychotics block also 5-HT receptors

5. Dopamine theory:dopaminergic systems in CNS

6. Dopamine theory:dopaminergic systems in CNS • Schema of dopamine pathways in the brain • Please se Rang-Dale p. 495 (Fig. 34.3)

7. Dopamine theory of schizophrenia • Symptoms of schizophrenia arise from hyperactivity of dopaminergic pathways in mesolimbic/mesocortical system • It was based on observation that 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 • There is a strong correlation between D2-antagonistic effects and antipsychotic action • Clinical response is reached when 80% of D2 receptors is occupied • Involvement of other D-receptors ??? D4 – specific antagonists are ineffective • Some theories suggest that the key issue may be the overactivation of D2 receptors in subsortical regions (positive symptoms) while activation of D1 receptors can be deficient (negative symptoms)

8. Symptom clusters of 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 agressvity • Disorganised speech • Stereotype/abnormal movements • Negative symptomes • 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

9. 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 causual • Pharmacologic– the mainstay of the treatment • Common mechanism of action: D2-antagonism • Additional mechanisms: antagonism on α1, M, H1, 5-HT2A/C • Adverse effects • Therapeutic effects • Nonpharmacologic – rather complementary (psychotherapy, psychosocial rehabilitation), electroconvulsive therapy

10. Pharmacotherapy of Schisophreniageneral aspects • Response in 70% of patients (30% are treatment resistant forms = big clinical issue) • Negative symptoms respond much less than positive symptoms (improved in atypical drugs) • The full antipsychotic effect deserve several weeks (3-4 weeks) to be reached. Only non-specific sedative and agressivity controlling effects can be induced immediately • Monotherapy is preferable, combinations only in resistant forms • In acute psychotic episode with strong agressivity and agitation typical antipsychotics might be useful (sedative effects, injectable forms are available) • 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

11. Pharmacokinetics of antipsychotics: • Most drugs can be given orally 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 hepatic biotransformation • - mostly CYP 450-dependent (exception ziprasidone) • * genetic polymorphisms (e.g., in CYP 2D6 - substrates risperidon) • Slow- release („depot“) preparations • areavailable, for several drugs. In these the active drug is esterified with heptanoic or decanoic acid and dissolved in oil. Given as an i.m. inj., the drug acts for 2-4 weeks. • e.g. Flupentixol decanoat, fluphenazine decanoat

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, α, H1, M and 5-HT2 receptor antagonists b) Dopamine and serotonin receptor antagonists -risperidone, ziprasidon c) D2-selective antagonists -sulpiride, amisulpiride

13. Classification of antipsychotics • Incisive vs. sedative (typical) antipsychotics • Incisive antipsychotics are 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 • Cause less extrapyramidal complications • Have improved efficacy against negative symptoms • Might be useful in treatment-resistant group of patients (especially clozapine) • Difference in overal efficacy ?

14. Adverse effects – A- type(predictable, dose dependent) I. Extrapyramidal motor disturbances - result from D2 receptor 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 - sever muscle spasms, very painful (occur within initial 24-96h) • Orofacial muscles (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 • 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?)

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

16. 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 V. Cardiovascular adverse reactions - Orthostatic hypotension - α-adrenoreceptors blockade - Drug induced QT syndrome (e.g., thioridazine) VI. Weight gain - probably related to 5-HT antagonism

17. Adverse effects – B –typeunpredictable • -neuroleptic malignant syndrome • Muscle rigidity is accompanied by a rapid rise in body temperature and • mental confusion. It is usually reversible, but death from renal or • cardiovascular failure occurs in 10-20% of cases. Discontinuation of therapy • and 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 ocuring in clozapine – its • use requires regular monitoring of blood cell counts. • - urticarial skin reactions(mainly phenothiazines) • Depositions • - in skin (in complex with melanine, gray discolouristion of skin) and • excessive sensitivity to UV light. • - in cornea/lens(vision distubances)