Positive symptoms of schizophrenia
- active auditory hallucinations
- paranoia
- delusions
Negative symptoms of schizophrenia
- depressive-like symptoms
- flat affect
- withdrawn
- amotivational
Dopamine hypothesis of schizophrenia
(1963) psychoses are the result of excessive dopamine activity in CNS; based in the observations that:
(1) dopamine antagonists alleviate psychosis
(2) sympathomimetics which cause dopamine release can induce psychosis
General characteristics of all antipsychotics
- orally administered (IM may be an additional option for some to be used in cases of acute exacerbation)
- extensive first-pass hepatic metabolism
- extensively plasma protein bound 95-98%; therefore very high potential for drug interactions with other plasma bound drugs
- generally long to very long half life (ex. chlorpromazine = 30 hrs)
- 70% of patients respond well to these drugs
- 1st generation antipsychotics all have anti-emetic effect (ex: promethazine, compazine)
“B-52” combination drug therapy
- haloperidol, lorazepam, diphenhydramine
- sometimes given IM for acute psychosis
- produces an acute neuroleptic syndrome of effects
neuroleptic syndrome
- sedation
- emotional quieting
- psychomotor slowing
- affective indifference / flat affect
neuroleptic malignant syndrome
- results from decreased dopamine activity
- pt’s nervous system becomes supersentitized to dopamine, this effect may not be reversible
- muscular rigidity, difficulty breathing/diaphragm rigidity, autonomic hyperactivity, high fever
- treatment is dilantin
- only occurs in 1% of pts taking antipsychotics, but among those affected 20-30% fatality
- unpredictable: may occur with therapeutic dosing; can happen with first dose or after chronic use
tardive dyskinesia
- an IRREVERSIBLE complication of LONG TERM use of dopamine antagonist therapy
- system becomes supersensitized to dopamine
- uncontrollable motor problems: facial fasciculations, lip smacking
- effects are opposite to parkinson’s; in parkinson’s pts have trouble moving, with t.d. pts have trouble not moving
Common side-effects of antipsychotics (list of 9)
- akathisias / nervous energy (common reason for noncompliance)
- dystonias (disorders of muscle tone)
- dyskinesias (disorders of muscle movement); includes tardive dyskinesia
- akinesia (absence of movement)
- drug induced parkinsonism
- neuroleptic malignant syndrome
- blood disorders in general (agranulocytosis with clozapine)
- endocrine: increased prolactin
- cardiovascular: orthostatic hypotension, similar effects to quinidine (class 1a anti-arrythmic, blocks Na channels, slows action potential, prolonged QT)
Effect of dopamine on prolactin
- dopamine normally inhibits prolactin
- dopamine antagonists increase prolactin levels (leads to a/dysmenorrhea and gynecomastia)
Common drug interactions with antipsychotics (list of 4)
- potentiation with CNS depressants
- interaction with OTC antihistamines (2nd generation antipsychotics have antihistamine effect; together produce synergistic sedation, slowed metabolism, increased appetite, and weight gain)
- caution with anti-emetics (some anti-emetics are 1st gen antipsychotics)
- interaction with other drugs that are highly plasma protein bound
1st generation antipsychotics
“typical” antipsychotics
- better for positive symptoms of schizophrenia, may exacerbate negative symptoms
MOA: dopamine type D2 receptor antagonists
3 classes: [NOTE: classes included for organizational purposes only, do not *need* to know for test] - phenothiazines - butyrophenones (haldol) - thioxanthenes
contraindications: blood dyscrasias, parkinsonism, chronic alcoholism, liver disease
Phenothiazines
- class of 1st gen antipsychotics
- structurally similar to tricyclic antidepressants; share many characteristics
- MOA: predominantly dopamine D2 antagonists, but also block alpha1, muscarinic, histamine receptors as well
- less D2 selectivity means greater alpha1 and muscarinic affinity (less motor/extrapyramidal effects, more autonomic effects)
- higher D2 selectivity means less alpha1/muscarinic affinity (more motor/extrapyramidal effects, less autonomic effects)
- low D2 selectivity phenothiazines
- moderate D2 selectivity phenothiazines
- high D2 selectivity phenothiazines
Low dopamine type 2 selectivity phenothiazines (list of 3)
- most autonomic effects among phenothiazines
- least extrapyramidal effects among phenothiazines
- chlorpromazine
- promazine (least effective)
- trifluopromazine
Moderate dopamine type 2 selectivity phenothiazines (list of 2)
- mesoridazine
- thioridazine
- seldom used, black box warning in usa, quinidine-like effect on heart
High dopamine type 2 selectivity phenothiazines (list of 3)
- least autonomic effects among phenothiazines
- most extrapyramidal effects among phenothiazines
- fluphenazine (decanoate formulation available/ very long acting ~2 months)
- perphenazine
- trifluoperazine
Haloperidol
- high to intermediate D2 selectivity
- decanoate formulation available
Thioxanthenes (list of 2)
chlorprothixene
thiothixene
- potent D2 receptor antagonists
- commonly used
2nd generation antipsychotics
“atypical” antipsychotics
- only weakly antidopaminergic
- 1st choice drugs for schizophrenia
- treat both positive and negative symptoms
- bc less effect on dopamine, less risk for tardive dyskinesia, neuroleptic malignant syndrome, and extrapyramidal effects
3 classes:
- heterocyclic antipsychotics
- serotonin 5HT-2A receptor antagonists
- partial dopamine receptor agonists
Heterocyclic antipsychotics (list of 6)
- clozapine: associated with impaired clotting and agranulocytosis; requires regular scheduled blood draws to assess drug level and granulocytes/wbc’s
- olanzapine: some incidents of sleepwalking; commonly given with a mood stabilizer for bipolar depression
- loxapine
- molindone
- pimozide: also indicated for tourette’s
- quetiapine: widely used, assoc with weight gain
5HT-2A receptor antagonists (list of 3)
- effective for controlling hallucinations, particularly auditory
- 5HT-2A agonists produce hallucinations (psychedelics i.e.. LSD, psilocybin etc)
- at higher doses can have haloperidol-like effects
- risperidone
- paliperidone: metabolite of risperidone; thought to antagonize 5HT-2A and D2 receptors
- ziprasidone
partial dopamine receptor agonists
- aripiprazole *
MOA: a partial agonist in the presence of a full agonist (excess dopamine) is an antagonist! so blocks enough excess dopamine to reduce psychosis but bc is a partial agonist reduces risk of extrapyramidal effects and neuroleptic malignant syndrome
- often used as an adjunct with another 2nd generation antipsychotic
- sometimes used as an adjunct for monopolar depression (unclear MOA and effectiveness in this context)
