medications + behavior: psychotic disorders

schizophrenia (onset, prev, genetic role)

• prevalence 

  • 1% 

• onset 

  • early adulthood 18-24 y/o

• family link

  • monozygotic twins have higher rates 

  • risk is greater when parent has schizo

  • NO schizo gene identified 

___________ role is very important in the etiology of schizo.

environmental

diathesis-stress model: schizo edition

“perfect storm” of

1. genetic susceptibility 

2. environmental stress

schizophrenia DSM-5 criteria

2+ sx

1. delusions 

2. hallucinations 

3. disorganized speech

4. disorganized behavior 

5. negative sx

delusions vs hallucinations

delusions

• misperception of something there

hallucinations

• something out of nothing

  • PET scans show speech centers (Brocas area) are activated when schizo hear “voices” NOT auditory centers

Broca’s Area + Wernicke’s Area 

Broca’s

• speech 

Wernicke’s

• hearing 

disorganized speech

loose associations, world salad

disorganized behavior

not goal-directed

positive symptoms 

presence (Schneiderian sx)

• hallucinations 

• delusions 

• disorganized speech

• disorganized/catatonic behavior

disorganized symptoms

erratic behavior

• speech

  • cognitive slippage

  • tangentiality

  • loose associations/derailment

• inappropriate affect/emotional expression (to situation)

• unusual behaviors

  • catatonia

catatonia 

wild agitation, waxy flexibility, immobility 

*specify if/if not present in schizo

negative symptoms 

absence 

• anhedonia 

  • inability to experience pleasure

• affect blunted 

  • mood tone, almost complete lack of facial expression

• alogia 

  • lack of speech

• avolition

  • difficulty making decisions 

• social withdrawal

historical: non-pharmacological tx of schizo 

• insulin shock

  • early 1930s, Sakel in Vienna

• electro-convulsive therapy 

  • late 1930s, Cerletti in Italy

• frontal lobotomy/leucotomy 

  • Egas Moniz in Portugal »» 1st frontal lobotomy on human in 1935; Nobel Prize 1949

  • Walter Freeman »» trans-orbital lobotomy

  • banned in 1967 w/ 4000 done

DA pathways 

• mesocortical 

  • cognitive/executive functions

  • VTA to PFC

• mesolimbic 

  • emotions; pleasure/reward

  • VTA to nucleus accumbens

• nigro-striatal

  • substantia nigra to striatum (basal ganglia »» caudate nucleus + putamen)

• tuberoinfundibular 

  • hypothalamus (limbic system) to pituitary

  • secretes prolactin

schizo pathology: revised dopamine hypothesis 

• decreased DA activity in PFC (DLPFC + VMPFC) »» hypofrontality 

• cognitive deficits + negative symptoms of schizo

*Davis + Kahn 1991 

schizo pathology: dopamine hypothesis lamnp

• excess DA activity in mesolimbic + nigrostriatal pathways in psychosis

• DA agonists (cocaine + amphetamine) induce psychotic symptoms »» particularly the positive ones

• when given L-Dopa (precursor to DA), Parkinson’s Disease patients’ symptoms improved BUT at higher levels of L-Dopa these same patients became psychotic

• positive schizophrenia symptoms are decreased w/ meds that block DA receptors

*Carlsson 1950s

critique of dopamine hypothesis

• antipsychotic meds reduce positive symptoms in many but not all schizo pts

• dissociative anesthetics + hallucinogens (PCP - phencyclidine and Ketamine - special k): produce positive + negative symptoms of schizo + associated cognitive deficits by blocking NMDA (glutamate receptor)

  • reduced NMDA receptor activity in subcortical regions (thalamus/hippocampus) »» excitotoxic glutamate activity in cortex »» negative symptoms of schizo

Thorazine 

Haldol

chlorpromazine (1st antipsychotic med)

haloperidol 

*1st gen antipsychotics/neuroleptics 

**major tranquilizers or typical antipsychotics 

Abilify

Clozaril

Seroquel

Risperdal

aripiprazole

clozapine

quetiapine

risperidone

*2nd gen antipsychotics/neuroleptics

**atypical antipsychotics

schizo: pharmacological tx

• phenothiazines

*most psychotics only address positive symptoms

Phenothiazines 

chlorpromazine (Thorazine)

accidentally discovered in 1950s as antinausea med 

mass psychiatric de-hospitalization in 1960s-1970s

Phenothiazines mechanisms

• D2 receptor antagonism (decrease DA transmission)

• therapeutic effect: must occupy 70-80% of D2 receptors

Phenothiazines SE

• block NE receptors

  • hypotension, tachycardia, sedation

• block ACh muscarinic receptors

  • dry mouth. dilated pupils, blurred vision, decreased sweating, memory impairment

• block histamine

  • sedative effects; antihistamine drowsiness

• blocking D2 receptors in basal ganglia »» DA receptor “supersensitivity” »» motor impairments

  • akathisia

  • extrapyramidal symptoms (EPS) »» severe dystonia TD tardive dyskinesia

akathisia 

subjective restlessness, compulsive need to move 

tardive dyskinesia

slow, involuntary movement + motor tics of the mouth, tongue, upper body

Non-phenothiazines

Haldol (haloperidol)

introduced in 1960s but approved by FDA in 1988

non-phenothiazines mechanisms

same as phenothiazines

non-phenothiazines side effects

same except for less affinity for histamine receptors (less sedating)

Clozapine

atypicals purported to manage both positive and negative sx of schizo

*1st Atypical/Second or New Generation of 1990

clozapine (Clozaril) I mechanisms

• binds less competitively than typical antipsychotics »» causes less disruption to DA transmission particularly in basal ganglia »» fewer movement disorder side effects

• occupies 75-80% of receptors

• antagonizes 5-HT2A receptors which ends up decreasing DA release

clozapine (Clozaril) side effects

• blocks histamine

  • very sedating

• blocks muscarinic (acetylcholinergic) receptors

  • dizziness, hypotension, high HR, dry mouth, constipation

• increased risk hyperglycemia + diabetes

• agranulocytosis

agranulocytosis

white blood cell (neutrophil) deficiency (prev 0.8% esp in 1st few months)

*can be fatal and requires careful monitoring for 1 year 

Risperdal (risperidone)

tx:

• schizo, BPD, ASD, + disruptive behavior in kids

• also used to supplement SSRIs and SNRIs w/ mild anxiety + sleep probs

Risperdal (risperidone) mechanisms

similar to clozapine (D2, 5HT2A, noradrenergic receptors)

binds weakly so less EPS at low doses

high doses similar to Typical antipsychotic meds

Risperdal (risperidone) side effects 

• low doses »» same as clozapine 

  • agranulocytosis

  • very sedating

• high doses »» same as Typical antipsychotics

  • anticholinergic side effects (dryness)

  • increased risk hyperglycemia, weight gain, DMT2

Abilify (aripiprazole) info and mechanisms 

partial DA agonist 

tx

• schizo and BPD, adjunctive use w/ treatment resistant depression

*Atypical antipsychotic 

Glutamate and Glycine Agonists: glutamate hypothesis of schizophrenia

• reduced NMDA receptor activity (eg from ketamine + PCP) »» positive, negative, + cognitive sx of schizo

• drugs that enhance glutamate NMDA activity esp helpful w/ negative symptoms

• problems w/ increasing glutamate: not specific and can increase excitotoxicity

• focus on glutamate receptors + glycine which modulates glutamate

*limited empirical evidence

measuring response to drugs: animal research

• amphetamine-induced psychosis

  • drug effects mimic psychosis + antipsychotic meds reduce psychotic symptoms

• prepulse inhibition PPI

  • prepulse warning tone followed by intense stimulus

  • prepulse normally inhibits startle response but not in animals w/ drug induced psychosis

  • antipsychotics (esp atypical antipsychotics) reverse this effect

PPI implications 

ppl w/ schizo have difficulty ignoring irrelevant stimuli 

• (+) hippocampal damage »» difficulty learning from experience 

schizo may be described by 

• Faulty Filter Hypothesis 

• Sensory-Motor Gating Deficit 

  • inability to “close the gate” on unimportant sensory infoeffi

efficacy + risk antipsychotics 

most patients improve w/ meds 

• initial response: 60-85% show improvement 

• eventual response: 75-85%

rare, potentially life-threatening reaction to antipsychotic meds:

• Neuroleptic Malignant Syndrome NMS 

  • high fever, muscle rigidity

  • rapid heart rate, delirium (extreme confusion)