The dopamine hypothesis states that the condition is associated with irregular, hyperactive dopaminergic signal transduction. People with schizophrenia tend to have an abnormally high level of dopamine (DA) or overactivation of the D2 receptors in their brain. There is also a genetic predisposition.
Diagnose is based on behaviors: positive symptoms are the addition of abnormal (hallucinations, delusions, and disorganized thinking and behaviors) and negative symptoms are lack of normal (lack of motivation, cognitive and functional impairment).
All antipsychotics carry a boxed warning for ↑ mortality in the elderly with dementia-related psychosis.
DA: is involved in reward mechanism, also controls voluntary movement, lack of DA is associated with Parkinson’s.
Drugs worsen schizophrenia
Parkinson meds (dopamine agonists): ↑ DA in the brain, 50% Parkinson patients experience hallucination or delusional thoughts.
Anticholinergics (more sedation, more side effects to antipsychotics.
Interferons, steroids, simulants: can alter mental status.
Hallucinogens and dissociative recreational drugs (lysergic acid diethylamide (LSD), ice, crack, cannabis, cocaine, Phencyclidine - PCP): worsening of mental status.
1st generation antipsychotics (Typicals)
Agents: Chlorpromazine, thioridazine, loxapine, perphenazine, fluphenazine (decanoate is Prolixin), haloperidol (Haldol, decanoate is IM only), droperinol (Inapsine)
MOA: block D2 receptors.
SE: sedation, movement disorders (EPS, TD, dystonia, NMS), orthostatic BP change, QT prolongation (higher with thioridazine), metabolic syndrome (hyperglycemia, elevated lipids, weight gain etc.), anticholinergic effects.
High potency (haloperidol) is associated with ↑ EPS, lower potency is associated with less EPS, but ↑ CV risk (orthostatic hypotension, tachycardia).
BBW: increased mortality in elderly (risk of fall).
EPS (extrapyramidal symptoms): low potency drugs have ↑ sedation and ↓ EPS (chlorpromazine), high-potency have ↓ sedation and ↑ EPS (haloperidol).
TD (tardive dyskinesia, facial movements) risk is higher in elderly, the effect is irreversible, the drug should be discontinued or switch to lower potency; Dystonia: prolonged muscle contraction, including oculogyric crisis (sustained upward eye deviation); Neuroleptic malignant syndrome (NMS): hyperpyrexia, muscle rigidity, fever, altered mental status, autonomic instability.
Supportive measures for movement side effects: dantrolene (a muscle relaxant), benztropine (Cogentin).
Due to decreased level of DA, if antipsychotic is used accidently in a patient with Parkinson (low level of dopamine), it can make the parkinsonian symptoms worse.
MOA: block dopamine receptors. Avoid dopamine blocking agents in elderly (Parkinson), e.g: metoclopramide for N/V in elderly, use an alternative.
SE: Sedation, movement disorders (too little DA), increased risk of metabolic syndromes (diabetes, elevated lipids, weight gain etc. Olanzapine, clozapine, risperidone, quetiapine), hyperprolactinemia (prolactin level is regulated by DA, most effects seen with risperidone, paliperidone, and haloperidol), anticholinergic effects, QT prolongation, orthostatic hypotension.
BBW: risk of death (risk of fall) in elderly, suicidality.
More effective at "negative" symptoms of Schizophrenia, less risk of EPS compared to 1st generation.
Just like the typicals, atypicals also carry QT prolongation risk, highest risk with thioridazine (1st generation), and ziprasidone/ iloperidone/ paliperidone/asenapine (2nd). Caution with drugs deplete K, Mg, that can increase arrhythmia risk: diuretic, AMG, cyclosporine, amphotericin.
Many are 3A4 substrate: Fluoxetine/paroxetine increase risperidone level 4 folds.
Clozapine (Clozaril, FazaClo ODT): effective but limited use due to agranulocytosis (initiate if WBC >3.5, ANC >2) and seizure; Lowest risk of EPS.
Aripiprazole: weight neutral, very long half-life, approved for depression. One of the lowest-risk agents in metabolic syndrome.
Quetiapine (Seroquel): eye exam for cataracts, known as "baby heroine" due to mind altering effect.
Risperidone: 1st drug approved for autism, EPS only at higher dose >6mg.
Paliperidone: active metabolite of risperidone, OROS delivery, dosed QD.
Asenapien (Saphris): SL form.
Psychosis in Parkinson
Pimavanserin (Nuplazid): agonist and antagonist at 5HT receptors, does not affect dopamine receptors, therefore does not worsen motor symptoms of Parkinson disease.
Quiz
The FDA has recently approved Risperdal-M Tab for which of the following indications?
Obsessive Compulsive Disorder b. Schizophrenia c. Irritability associated with Autism d. Bipolar mania e. Parkinsonism
Answer. BCD. Risperdal M-Tab (ODT) is indicated for the acute and maintenance treatment of schizophrenia. In 2006 FDA approved Risperdal (Risperidone) orally disintegrating tablets, an adult antipsychotic drug, for the symptomatic treatment of irritability in autistic children and adolescents. It is the first approved antipsychotic to treat behaviors associated with autism in children. These behaviors are irritability, and include aggression, deliberate self-injury, and temper tantrums.
