Schizophrenia

psychotic disorder with positive and negative symptoms

clear sensorium; marked thought disorder

1% of population across cultures

patients used to be kept in insane asylums under cruel conditions and subjected to experiments

complex genetic and environmental etiology

onset between 18-35 years of age

Positive symptoms in psychotic disorders

• hallucinations (auditory most common)
• delusions (may be paranoid)
• bizarre behavior
• disorderd thoughts (loose associations)
• disordered speech--word salad, poor syntax

Negative symptoms in Schizophrenia

• flat/blunted affect
• poverty of speech/speech content
• avolition/apathy
• anhedonia (loss of pleasure)
• social withdrawl
• catatonia

Year phenothiazines first prescribed and significance

1955

numbers of institutionalized schizophrenics dropped precitiptously

Dopamine Hypothesis

psychotic symptoms caused by excessive dopamine activity

all antipsychotics block D2 receptors (typical and atypical)

older, foundational theory about neurotransmitter dysfunction in schizophrenia

overly simplistic

increased dopamine recceptor density in brains of schizophrenic patients

Serotonin Hypothesis

newer theory about psychotic disorders postulating that excessive serotonin activity contributes to psychosis

newer Atypical Antipsychotics block 5-HT receptors in addition to D2 recptors

negative symptoms more responsive to serotonin-blocking atypical antipsychotics vs. older drugs

Drugs that can aggravate psychotic symptoms

by increasing dopamine activity

1. L-DOPA--converted to dopamine

2. Amphetamines--inhibit dopamine reuptake pumps

3. Apomorphine--activates dopamine receptors (no opioid activity)

Drugs that can stimulate serotonin receptors to cause hallucinations

LSD

Mescaline

Typical Antipsychotics (Neuroleptics)

A. Phenothiazines

1.chlorpromazine

2. thioridazine

3. fluphenazine

B. Non-phenothiazine typical antipsychotics

1.Haloperidol

2. Molindone

3.Thiothixene

main activity via D2 dopamine receptor blockade, many other receptors also affected

major consistent side effect: extrapyramindal signs--motor disturbances

Phenothiazines

typical antipsychotics

MOA: D2 receptor blockade-->reduced positive psychotic symptoms

1.chlorpromazine, low potency, high sedation

2. thioridazine, intermediate potency

3.fluphenazine, high potency, more risk for extrapyramidal effects

developed as sedating antihistamines in 1950s and accidentally found to have antipsychotic action

structural homology with tricyclic antidepressants

Phenothiazine Side Effects

side effects (and associated receptor blockade):

1. hypotension (alpha-adrenergic)

2. sedation (H1)

3. extrapyramidal motor sx and hyperprolactinemia (D2)

4. anticholinergic sx--dry mouth, urinary retention, blurred vision (muscarinic)

5. lowered seizure threshold, weight gain, temperature dysregulation

Phenothiazine Drug Interactions

• potentiate anticholinergics
• pontentiate CNS depressants (alcohol, benzos, opioids, barbiturates)
• potentiate alpha blockers
• exacerbate risk of hypotension when used with nitrates (angina) or sildenafil (erectile disfunction)

Extrapyramidal Effects

common adverse effects with typical antipsychotics

if seen, reduce dosage or change medications!

1. Pseudoparkinsonism with rigidity, bradykinesia, tremor, petit-pas gait (small shuffling steps)

onset 5-30 days after initiating drug

2. Akathisia=motor restlessness, inability to remain still not related to anxiety

onset 5-60 days after initiating drug

3. Tardive dyskinesia: involuntary orofacial, arm, hand, or limb movements

onset at least 1 year after drug initiation

may become permanent

4. Neuropleptic malignant syndrome: severe muscle rigidity, hyperthermia, unstable BP, agitation, confusion

emergency!

onset within 30 min. of drug administration, especially haloperidol

Neuropleptic Malignant Syndrome

may be considered a subtype of extrapyramidal effect

medical emergency affecting 5% of patients treated with IM haloperidol (haldol)

severe muscle rigidity, hyperthermia, unstable BP, agitation, confusion

onset within 30 min. of drug administration, residual effects for 3-4 weeks

treat with dantrolene (muscle relaxant) and bromocriptine (dopamine agonist)

Chlorpromazine (thorazine)

phenothiazine typical antipsychotic

prototype drug

low potency, higher sedation, relatively lower risk for extrapyramidal effects

MOA: D2 dopamine receptor blockade improves psychotic symptoms (especially positive signs)

side effects: hypotension, sedation, decreased seizure threshold, abnormal temperature regulation, weight gain, dry mouth, urinary retention, blurred vision (anticholinergic sx), hyperprolactinemia (galactorrhea + LH and FSH suppression), extrapyramidal effects

drug interactions: potentiates anticholinergics, CNS depressants, alpha-blockers, nitrates, and sildenafil

Thioridazine (mellaril)

phenothiazine typical antipsychotic

intermediate potency, intermediate risk for sedation and extrapyramidal effects

MOA: D2 dopamine receptor blockade improves psychotic symptoms (especially positive signs)

side effects: hypotension, sedation, decreased seizure threshold, abnormal temperature regulation, weight gain, dry mouth, urinary retention, blurred vision (anticholinergic sx), hyperprolactinemia (galactorrhea + LH and FSH suppression), extrapyramidal effects

drug interactions: potentiates anticholinergics, CNS depressants, alpha-blockers, nitrates, and sildenafil

Fluphenazine (prolixin)

phenothiazine typical antipsychotic

high potency, higher risk for extrapyramidal effects, less sedation

MOA: D2 dopamine receptor blockade improves psychotic symptoms (especially positive signs)

side effects: hypotension, sedation, decreased seizure threshold, abnormal temperature regulation, weight gain, dry mouth, urinary retention, blurred vision (anticholinergic sx), hyperprolactinemia (galactorrhea + LH and FSH suppression), extrapyramidal effects

drug interactions: potentiates anticholinergics, CNS depressants, alpha-blockers, nitrates, and sildenafil

Haloperidol (Haldol)

non-phenothiazine typical antipsychotic

MOA: D2 receptor blockade-->reduces positive psychotic symptoms

high potency, fewer autonomic side effects

high incidence of extrapyramidal effects

increased association with neuroleptic malignant syndrome, especially if given IM

Molindone (moban)

non-phenothiazine typical antipsychotic

MOA: D2 receptor blockade-->reduces positive psychotic symptoms

high potency, fewer autonomic side effects

high incidence of extrapyramidal effects

Thiothixene (navane)

non-phenothiazine typical antipsychotic

MOA: D2 receptor blockade-->reduces positive psychotic symptoms

less potent vs. phenothiazines

lower incidence of extrapyramidal side effects

Atypical Antipsychotics

block 5-HT (serotonin) receptors at least as well as D2 (dopamine) receptors

newer antipsychotic drugs, more success in treating positive and negative symptoms

now first line drugs for psychotic disorders/schizophrenia

major adverse effects are hyperglycemia, obesity, metabolic syndrome, and type 2 diabetes

no difference in efficacy or compliance vs. older typical antipsychotics but more expensive

Clozapine (clozaril)

prtotype atypical antipsychotic

MOA: blocks 5-HT2, D2, and alpha receptors

Adverse effects: hyperglycemia, obesity, orthostatic hypotension (alpha blockade), somnolence, lowered seizure threshold, agranulocytosis

agranulocytosis unique to clozapine, appears after 4-6 weeks of treatment in 1% of patients, can lead to life-threatening infections, white blood cell counts must be monitored frequently while on this drug

Olanzipine (zyprexa)

atypical antipsychotic

MOA: blocks 5-HT2, other 5-HT receptors, D2, and alpha receptors

Adverse effects: hyperglycemia, obesity, orthostatic hypotension (alpha blockade), somnolence

approved for use in bipolar disorder and schizophrenia

Risperidone (risperdal)

atypical antipsychotic

MOA: blocks 5-HT2, D2, H1 and alpha receptors

Adverse effects: initial sedation (due to histaminergic blockade but tolerance develops in a few weeks) hyperglycemia, obesity, dose-dependent hypotension-->reflex tachycardia, prolonged QT interval-->cardiac arryhthmias

contraindicated in patients with cardiovascular problems

first line drug at central state hospital in Ky

Aripiprazole (Abilify)

atypical antipsychotic

unique MOA: mixed agonist and antagonist activity at D2 and 5-HT receptors

toxicity: somnolence, orthostatic hypotension, hyperglycemia, obesity (though perhaps less marked than with the other atypical neuroleptics)

also approved for bipolar disorder/mania

Quetiapine (seroquel)

Atypical neuroleptic (antipsychotic)

 MOA: blocks 5-HT2, 5-HT1A, D2, D1 and H1 receptors

Toxicity: marked somnolence, orthostatic hypotension, hyperglycemia, obesity

Ziprasidone (geodon)

atypical antipsychotic

MOA: blocks 5-HT2, D2 and alpha receptors

Toxicity: somnolence, orthostatic hypotension, hyperglycemia, obesity,  and prolongation of the QT interval leading to cardiac arryhthmias and sudden death

reserved for patients unresponsive to other drugs

Glutamate hypothesis

latest theory about neurotransmitter dysfunction in psychotic disorders

proposes that decreased activity of NMDA glutamate receptors in the neocortex contributes to schizophrenia

new antipsychotic drugs in clinical trials are NMDA superagonists and glycine transport inhibitors

Evidence for the Glutamate Hypothesis

1. NMDA blockers ketamine and PCP induce positive and negative psychotic symptoms in abusers

2. single nucleotide polymorphisms in the brains of some schizophrenics reduce glutamate binding to NMDA receptors

3. NMDA receptors require co-stimulation by glycine, and giving large doses of glycine with clozapine has been found to reduce negative symptoms

Indications for Antipsychotic Drug Therapy

• Schizophrenia
• Biopolar disorder with psychotic features
• Tourette's syndrome
• Disturbed behavior in dementia
• Antiemesis

Lithium

older mood stabilizing drug used in bipolar disorder (but not in schizophrenia)

MOA: unclear but probably involves inositol triphosphate 

Drug interactions: 1. thiazide diuretics-->sodium depletion

2. NSAIDs--> increased lithium reabsorption, increased risk for toxicity

narrow therapeutic index