SCZ Flashcards
SCZ and psychotic disorders exist _____
along a spectrum of severity with
Positive symptoms meaning
gain of function
Positive symptoms examples
Delusions Hallucinations Disorganized speech Grossly disorganized or catatonic motor behaviour
Negative symptoms meaning
loss of function
Negative symptoms examples
Avolition
Social deficits
Flattened affect
Cognitive deficits
presence of ____ symptoms makes SCZ unique
Positive symptoms; most mental disorders primarily are loss of function (have negative features)
Spectrum of SCZ and psychosis (from least to most severe)
Scizotypal personality disorder –> delusional disorder –> brief psychotc disorder –> schizophreniform disorder –> SCZ –> schizoaffective disorder
T/F scz stays the same throughout life
FALSE
Schizophrenia is a persistent, progressive disorder (negative symptoms)
with periodic relapse into psychosis (positive symptoms)
Lifetime prevalence
1%
The societal cost of SCZ (heavy use of resources due to:)
- Schizophrenic patients may account for
up to 50% of repeat hospital
admissions* and 25% of inpatient beds - Vastly overrepresented in prison and
homeless populations - high suicidality
- 50% co-morbid with substance abuse
- psychiatric comorbidities–mood and anxiety disorders
- decreased life expectancy (of 10-25 years)
Co-morbidities with SCZ
- high suicidality
- 50% co-morbid with substance abuse
- psychiatric comorbidities–mood and anxiety disorders
Neuroleptic development: first antipsychotic
Chlorpromazine
Chlorpromazine
1at antipsychotic developed in 1950 as an anti‐histamine and sedative
◦ First synthesis Dec 1950 –> human use in 1951–> Licensed to Smith Kline & French (GSK) 1953
Neuroleptic drug definition
Drugs affecting pathological behaviour
Societal/medical effect of Chlorpromazine (CPZ)
- Contributed directly to medicalization of mental illness
- Recognition of mental illness as a consequence of an underlying biological
deficit
Chlorpromazine actions–main systems
Anti‐cholinergic
Anti‐histaminergic
Anti‐adrenergic
Anti‐dopaminergic
Chlorpromazine side effects
Anticholinergic: Dry‐mouth, blurred vision,
constipation, weight gain
Anti-histaminergic: sedative, anti-emetic
ANti-adrenergic: Lowered blood pressure,
tachycardia, vertigo, incontinence,
sexual dysfunction
Anti-dopaminergic: actual antipsychotic effects (reduce positive symptoms), extrapyramidal side effects and hyperprolactinemia
Main effects of CPZ (bolded)
Weight gain (anti-cholinergic) Sedation (anti-histaminergic) Antipsychotic effects (anti-DA) Extrapyramidal effects (anti-DA) Hyperprolactinaemia (anti-DA)
The Dopamine hypothesis
SCHIZOPHRENIA RESULTS FROM EXCESSIVE DOPAMINERGIC ACTIVITY SPECIFICALLY IN THE MESOLIMBIC PATHWAY.
this theory arose from CPZ ‘s efficacy
Mesolimbic dopamine is
proposed to mediate _____
SALIENCE
Motivational salience –addictions
Sensory salience – sensory gating
Too much dopamine on the mesolimbic pathway causes SCZ due to…
Excess dopamine activity leads the patient to perceive voices, sounds, and imagery
as inappropriately salient
Excess da –> ___ salience –> interpreted as ___ & ____
increased salience; interpreted as delusions and hallucinations
i.e. False significance assigned to internal and external stimuli are interpreted as delusions and hallucinations
Issues with the DA hypothesis
Dopamine is hyperactive in the mesolimbic but hypoactive in the cortex
◦ Presynaptic changes in dopamine synthesis
◦ Expect common changes in both mesolimbic and mesocorticolimbic pathways
◦ Postsynaptic targets of antipsychotics
Causality of dopaminergic changes is unclear!!
Lack of clear evidence for dopaminergic neuropathology in SCZ
Dopamine correlates well with positive symptoms (i.e. psychosis) BUT Poor correlation with negative symptoms
DA drugs have limited effects on ___ symptoms
Negative; which are usually the most debilitating
Dopamine hypothesis 2.0
SCHIZOPHRENIA RESULTS FROM A COMBINATION OF SUBCORTICAL DOPAMINERGIC HYPERACTIVITY AND CORTICAL DOPAMINE HYPOACTIVITY.
Dopamine hypothesis 3.0
Schizophrenia results from combined genetic and environmental insult resulting in altered neurodevelopment, including subcortical dopaminergic hyperactivity and psychosis.
1st generation antipsychotics AKA ____ antipsychotics are characterized by ____
‘ TYPICAL’ ANTIPSYCHOTICS
CHARACTERISED BY ANTAGONISM OF THE DOPAMINE D2 RECEPTOR
Phenothiazines examples
1st gen
Clorpromazine; thoridazine, Trifluoperazine, Perphenazine
Phenothiazines–defintion
1st gen; Low potency antipsychotics have increased anticholinergic side effects (dry mouth, constipation, weight gain) and decreased extrapyramidal side effects
Thioxanthenes
Modified ring structure from
phenothiazines ( N –> C)
Piperazine derivatives are potent antipsychotics
Thioxanthenes
1st gen
Modified ring structure from
phenothiazines ( N –> C)
Piperazine derivatives are potent antipsychotics
Butyrophenones and diphenylbutylpiperidines
1st gen Butyrophenones (haloperidol) are high potency antipsychotics – common ‘front line’ antipsychotics • BUT High risk of extrapyramidal side effects Diphenylbutylpiperidines (pimozide) – derived from butyrophenones – have longer duration of action
Which is has a longer duration of action Butyrophenones or diphenylbutylpiperidines
diphenylbutylpiperidines (a derivative of Butyrophenones)
Which is has a longer duration of action Butyrophenones or diphenylbutylpiperidines
diphenylbutylpiperidines (a derivative of Butyrophenones)
Extrapyramidal side effects (EPS)
Akinesia – inability to initiate movement
Akathisia – inability to remain motionless
Acute dystonia – sustained muscle contraction, twisting and repetitive movements
Pseudoparkinsonism – fixed (non‐progressive) Parkinsonism without degeneration of dopaminergic neurons
Tardive dyskinesia – involuntary, repetitive motor disorder that persists after discontinuation of antipsychotic therapy
Akinesia
EPS
inability to initiate movement
Akathisia
EPS
inability to remain motionless
Acute dystonia
EPS
sustained muscle contraction, twisting and repetitive movements
Pseudoparkinsonism
EPS fixed (non‐progressive) Parkinsonism without degeneration of dopaminergic neurons
Tardive dyskinesia
EPS
involuntary, repetitive motor disorder that persists after discontinuation of antipsychotic therapy
Degeneration of dopaminergic neurons in the
______ is central to the pathophysiology of
Parkinson’s disease, with symptoms including…
nigrostriatal system
causing tremors, rigidity, forward‐flexed posture and shuffling steps, bradykinesia (slowed movement)
Antipsychotic blockade of __ receptors in the ____ is responsible for extrapyramidal side‐effects
D2; in the striatum
DA in the _____ pathway suppresses the release of _____ from the pituitary; antipsychotic antagonism of D2 causes ____
tuberoinfundibular pathway; prolactin; Hyperprolactinemia can result from antipsychotic
treatment: causes Amenorrhea (♀), infertility(♂/♀), sexual dysfunction (♂/♀), hypogonadism (♂), spontaneous lactation (♂/♀)
@nd gen antipsychotics aka ___ are characterized by
‘ATYPICAL’ ANTIPSYCHOTICS
CHARACTERIZED BY ANTAGONISM OF THE 5HT2A RECEPTOR AND D2R
[Tri/tetra]cyclics`
2nd gen Dibenzodiazepine antipsychotics Effects on 5HT2AR proposed to explain efficacy against negative symptoms CLozapine, N‐desmethylclozapine (active metabolite with affinity for D2R) and Olanzepine (5HT2A and D2R affinity – high rate of weight gain and diabetes)
CLozapine
the first atypical AP; a Dibenzodiazepine antipsychotics • High affinity antagonism of 5HT2AR • Low affinity for D2R • Possible effects on D‐serine (NMDAR co‐agonist) and GABABR • Risk of agranulocytosis and cardiac toxicity
WHy do [Tri/tetra]cyclics work better on negative symptoms
Due to effects on 5HT2AR
• N‐desmethylclozapine – active metabolite with affinity for D2R
• Olanzepine – 5HT2A and D2R affinity – high rate of weight gain and diabetes
Quetiapine
2nd gen; [Tri/tetra]cyclics
Quetiapine – 5HT2A and moderate D2 antagonist
• Norquetiapine – active metabolite – D2 affinity and
norepinephrine reuptake inhibitor
Asenapine
2nd gen; [Tri/tetra]cyclics
extremely high (sub‐nM) affinity for 5HT2A, strong D2
antagonist – low weight gain
Risk of death in dementia patients
Benzisoxazoles–exmaples
Risperidone, Paliperidone (palmitate), Ziprasidone, Lurasidone, Iloperidone
Risperidone
Risperidone – strong 5HT2A inverse agonist, D2 antagonist
• High risk of metabolic and prolactin side effects, high EPS relative to other atypicals
• Paliperidone (palmitate) – active metabolite marketed as an antipsychotic – palmitate ester allows long‐release injectable formulation (monthly)
Other Benzisoxazoles
Ziprasidone – low weight gain, high cardio side effects Lurasidone – low cognitive side effects Iloperidone – low weight gain, moderate EPS AND paliperidone (palmitate) – active metabolite of risperidone marketed as an antipsychotic – palmitate ester allows long‐release injectable formulation (monthly)
Aripiprazole
2nd gen (but other) partial agonist at D2 and 5HT1A, weak partial agonist at 5HT2A (functional antagonist) • Minimal sedation and metabolic side effects
Relative efficacy of antipsychotics
With the exception of clozapine, most atypical and typical antipsychotics have comparable performance.
Previous assertions that atypical antipsychotics are superior have been questioned.
Are atypical psychotics better?
Not necessarily
Previous assertions that atypical antipsychotics are superior have been questioned.
• 5HT2A affinity does not necessarily correlate with
efficacy
ex. Asenapine – extremely high 5HT2A affinity has moderate efficacy
Tolerability of antipsychotics
Haloperidol (typ) has the highest rate of EPS and highest
overall discontinuation
Potent D2 antagonists (haloperidol, risperidone) have
highest rates of hyperprolactinaemia
Olanzepine (atyp) has the highest rate of weight gain
___ has the highest rates of discontinuation largely due to ___ side effects
Haloperidol; EPS
Potent D2 antagonists (haloperidol, risperidone) have
highest rates of hyperprolactinaemia
Glutamate hypothesis–why?
- role of NMDA receptor in SCZ
- Multiple genetic risks associated with excitatory synaptic function & plasticity
- NMDAR hypofunction in SCZ; current drugs increase - — NMDAR-antags cause positive and negative symptoms
Evidence increasing glutamate may be helpful
- NMDA antagonists (ketamine, phencyclidine [PCP]) produce positive and negative symptoms
- Haloperidol (1st gen antipsychotic) increases NMDA receptor density and extracellular glutamate concentrations
- Elevated glutamate levels are reported in patients taking antipsychotics
- Oral administration of glycine (NMDA receptor co‐agonist) reported improving negative symptoms in patients
D-serine
Potential future drug
◦ Potent co‐agonist at the NMDAR glycine site
◦ Improves negative, positive, and cognitive symptoms as an adjunctive therapy
◦ Clozapine shown to increase release of D‐serine from astrocytes
◦ D‐amino acid oxidase (DAAO) activity has been reported to be elevated in SCZ
◦ Risperidone is an antagonist at DAAO
Immune function in SCZ–why we could target it
Numerous genetic and environmental risks converge on immune function
◦ Polymorphisms in Major Histocompatibility Complex
◦ Pre‐ and peri‐natal risks such as maternal infection,
stress, nutrition, and delivery complications
Immuned cells of CNS regulate…
development and plasticity
◦ Critical for establishing E/I balance (that is messed up in SCZ)
◦ Regulate synaptic turnover of glutamate, GABA,
and D‐serine
Anti‐inflammatory minocycline
reported efficacy as an adjunctive treatment
support immune function
Cannabidiol
Antipsychotic effects of cannabidiol are suggested to involve neuroinflammation
Neurochemistry of SCZ
◦ Dopamine hypothesis
◦ Glutamate and GABA (NMDA or E/I imbalance)
◦ Immune hypothesis
Typical vs Atypical
Typical’ (1st generation) antipsychotics
◦ Potent D2 antagonists
◦ Effective against positive symptoms
Atypical’ (2nd generation) antipsychotics
◦ 5HT2A antagonists
◦ Some efficacy against negative symptoms