Psychopharmacology--Schizophrenia

Pathways involved in schizophrenia

-Arcuate nucleus to median eminence (prolactin) -Substantia nigra (midbrain) to corpus striatum (EPS tract) -Midbrain (VTA) to limbic structures (mesolimbic) and the prefrontal cortex (mesocortical)

Neurological effects

-Increased risk of seizures -Parkinsonism related to decreased dopamine activity in striatum -Thioridazine (Mellaril) and atypical antipsychotics less likely to produce such effects --muscarinic receptor affinities

Several including Thorazine block muscarinic receptors

-Memory impairment, confusion -blurred vision -constipation -xerostomia -decreased sweating

Direct neurological effects (1)

-Parkinsonism common (up to 95% of pts receiving typical antipsychotics) --Bradykinesia shuffling gait --Tremor and rigidity

Direct neurological effects (2)

Acute dystonia -muscle spasms in face, neck, tongue -can be treated with anti-parkinson's agents (benztropine; congentin) Akathisia -motor restlessness -reduce dosage -treat with anti-parkinson's agents

Blockade of D2 receptors improves positive symptoms of schizophrenia and..

Also suppresses hypothalamic function -Delays menses and ovulation -Produces poikilothemia (can't regulate your own body temperature) -increase lactation and breast engorgement (duet increase prolactin release)

Elevated dopamine activity associated with schizophrenia

Amphetamine and L-DOPA can produce symptoms of schizophrenia in non-schizophrenic patients -Neuroleptics block dopamine receptor activity (primarily D2) -Correlation between affinity for dopamine receptors and antipsychotic activity

Main approach for the tx of schizophrenia?

Antipsychotics -Decrease relapse rates -Increase verbal skills -Decrease positive symptoms (less effective with negative symptoms

Anti-parkinsonism drug effective

Artane Cogentin Kemadrin Akineton

Prognosis:

Chance for full recovery is low More likely to occur within first few years of therapy Social recovery is more common

Objective in treating schizophrenia?

Clinical setting--treat active psychosis Outside the clinic--prevent relapse and maintain social interactions

Compounds can be selected for sedative properties

Compounds with higher affinity for H1 receptors produce sedation --potentially useful for highly agitated patients --Phenothiazine, Clozaril, Olanzapine (Zyprexa) Compounds with lower affinity for H1 receptors are less sedating --more appropriate for withdrawn patients --Haldol, Risperdal, Stelazine

Neurochemical abnormalities (dopamine hypothesis)

Dopamine Hypothesis (Arvid Carlsson) ---Elevated dopamine activity associated with schizophrenia Carlsson--received the 2000 nobel prize in physiology or Medicine. His work helped establish dopamine as a neurotransmitter -Identified mechanism of action for antipsychotic drugs

Compounds with higher affinity for a1 receptors produce hypothension

Mellaril and Thorazine have the highest a1 receptor affinity -Seroquel, Clozaril, and Risperdal also have high a1 receptor affinity -Haldol, Zyprexa, and Stelazine have lower a1 receptor affinity

Many antipsychotics (thorazine, Clozaril, Mellaril) inhibit a1 receptors...causes..

Miosis (pupil constriction) Orthostatic hypotension

+ or - symptoms respond to atypical antipsychotics

Negative and positive symptoms may respond to atypicals

Direct neurological effects (3) (more rare)

Neuroleptic malignant syndrome (rare) -Extreme Parkinson's symptoms -Catatonia, stupor, fever, unstable blood pressure -Immediately discontinue antipsychotic -treat with dantrolene (skeletal muscle relaxant and used to treat hyperthermia) or bromocriptine (DA agonist, used in tx of amenorrhea and restrains prolactin Tardive Dyskinesia -abnormal repetitive movements of the face, tongue, and mouth -Choreoathetosis or dystonia -develops after months or even years of treatment -more frequent in older patients

H1 receptor blockade

Phenothiazine and thioxantines Clozaril and related compounds Promethazine was one of the earliest antihistamines -results in sedation -Cardiovasular effects --hypotension, prolonged QT and PR intervals, Thioridazine (melario) can produce ventricular arrhythmias and death

+ or - symptoms respond to classical antipsychotics?

Positive

Compounds that can be selected for reduced EPS effects

Thioridazine (melario) and atypical antipsychotics produce fewer EPS -Generally have significantly higher affinity for 5-HT2 and M1 receptors -Ratio of 5-HT2:D2 affinity is lower Compound with high affinity for muscarinic receptors produce fewer EPS (except for Risperdal)

Symptoms are classified into what two categories?

Type I (positive symptoms) -Hallucinations -Delusions -Disordered thought Type II (negative symptoms) -Lack of motivation -Social withdrawal -Blunted affect -Impoverished speech

Classical antipsychotics exert their action through...

blocking dopamine receptors in the CNS -D2 receptors implicated in both therapeutic and adverse effects -Atypicals (clozapine) have lower affinity for D2 receptors D4 receptors may be an important target