PSY7 Schizophrenia

Which of these is not a disorder in which psychosis is defined?

Schizophrenia: ~ [blank_start]1[blank_end] % of population, psychotic illness, mostly [blank_start]young[blank_end] people, [blank_start]chronic[blank_end] (regular/irregular psychotic episodes), lifelong and highly disabling. Positive and negative symptoms: - A positive symptom is one that [blank_start]adds[blank_end] a behavior, thought or feeling. Positive symptoms associated with schizophrenia also occur in other disorders such as [blank_start]bipolar[blank_end], psychotic depression, and [blank_start]Alzheimer[blank_end]'s. Positive symptoms are – [blank_start]delusions[blank_end] (paranoid), hallucinations, thought [blank_start]disordered[blank_end], other abnormal behaviors e.g. aggression. - Negative symptoms [blank_start]take away[blank_end] a behavior, thought or feeling. Negative symptoms – flattened [blank_start]emotional[blank_end] response, social [blank_start]withdrawal[blank_end], apathy, anhedonia. Cognitive symptoms: - [blank_start]Executive dysfunction[blank_end] - poor methodical planning in brain makes basic tasks difficult - Difficulty representing and maintaining [blank_start]goals[blank_end], allocating [blank_start]attention[blank_end], evaluating/monitoring performance - Impaired [blank_start]verbal[blank_end] fluency These are the best predictor of outcome.

Burden of illness • 25-50% attempt suicide and [blank_start]10[blank_end]% eventually succeed • Mortality rate 8 times higher than general population due to high rate of [blank_start]CV disease, suicide[blank_end] etc, • Life expectancy [blank_start]25-30[blank_end] years shorter than the general population • Patients - early onset, intellectual [blank_start]development[blank_end], relationships, risk of suicide, stigma, self treatment: [blank_start]drugs, alcohol and smoking[blank_end] • Family/Care Giver - stressors, financial [blank_start]cost[blank_end], pressure on [blank_start]relationships[blank_end] • Community – healthcare, economic, stigma • Duration of [blank_start]untreated psychosis[blank_end] (DUP) has major impact on outcomes

Early symptoms indicating the onset of schizophrenia: • Worrisome drop in [blank_start]grades or job performance[blank_end] • New trouble [blank_start]thinking clearly or concentrating[blank_end] • Suspiciousness, [blank_start]paranoid[blank_end] ideas or uneasiness with others • Withdrawing socially, spending a lot more time [blank_start]alone[blank_end] than usual • Unusual, overly intense new [blank_start]ideas[blank_end], strange feelings or having [blank_start]no[blank_end] feelings at all • Decline in [blank_start]self-care or personal hygiene[blank_end] • Difficulty telling reality from fantasy • Confused [blank_start]speech[blank_end] or trouble communicating

Match the symptoms to the region: Positive symptoms - [blank_start]mesolimbic pathway[blank_end] Affective symptoms (anxiety, suicidality) - [blank_start]ventromedial prefrontal cortex[blank_end] Aggressive symptoms - [blank_start]orbitofrontal cortex, amygdala[blank_end] Cognitive symptoms - [blank_start]dorsolateral prefrontal cortex[blank_end] Negative symptoms - [blank_start]mesocortical pathway, prefrontal cortex[blank_end]

Diagnosis • Based on patient and often family [blank_start]interviews[blank_end] following presentation of first psychotic episode • Clinical status/rating determined using psychiatric examination with [blank_start]Positive and Negative Symptom Score[blank_end] (PANSS) and Clinical Global Impression scales (CGI) - commonly use Diagnostics and Statistics Manual (DSM-V) or ICD-11 • Also use At Risk Mental State (ARMS) Brief Psychiatric Scale (BPS) • [blank_start]Psychosis[blank_end] not otherwise specified often in patient notes due to [blank_start]stigma[blank_end] associated with the term schizophrenia

Five dopaminergic pathways: a) [blank_start]Nigrostriatal[blank_end] – controls motor function/movement b) [blank_start]Mesolimbic[blank_end] - pleasurable sensations, euphoria & delusions/hallucinations (positive sypmtoms) c) [blank_start]Mesocortical[blank_end] - mediates cognition and affect (and negative symptoms) d) [blank_start]Tuberoinfundibular[blank_end] - prolactin secretion e) there's another one he didn't tell us it's name i don't think it's important??

Schizophrenia - the [blank_start]Integrated[blank_end] Dopamine Hypothesis. Majority of symptoms explained by dysregulation of dopaminergic pathways: - [blank_start]High[blank_end] activity of mesolimbic pathway explains pos symptoms - [blank_start]Low[blank_end] activity of mesocortical pathways explains cog, aff, neg symptoms - [blank_start]Normal[blank_end] activity of nigrostriatal and tuberoinfundibular

Order these drugs from lowest affinity for D2 Rs (low potency, to highest affinity for D2 Rs (high potency); low being 1 and high being 4. 1. [blank_start]Haloperidol[blank_end] 2. [blank_start]Prochlorperazine[blank_end] 3. [blank_start]Clozapine[blank_end] 4. [blank_start]Chlorpromazine[blank_end]

NMDA receptor hypofunction hypothesis: There are NMDA receptors in the brain. NMDA receptors in the [blank_start]cortical brainstem[blank_end] have glutamate projections. A glutamate projection is a [blank_start]descending[blank_end] pathway that uses glutamate, an [blank_start]excitatory[blank_end] neurotransmitter. Schizophrenia may be caused by [blank_start]low[blank_end] activity in these glutamate projections. When the glutamate projections are [blank_start]hypo[blank_end]-active, downstream [blank_start]inhibition[blank_end] of the mesolimbic DA pathway does [blank_start]not[blank_end] occur, meaning the [blank_start]mesolimbic[blank_end] DA pathway is [blank_start]hyperactive[blank_end]. This causes positive symptoms. Also low [blank_start]activity[blank_end] of the excitatory NT glutamate means [blank_start]tonic excitation is lost[blank_end], and [blank_start]mesocortical[blank_end] DA pathways become [blank_start]hypoactive[blank_end]. This may cause the cognitive, negative, and affective symptoms. TLDR; Low activity of [blank_start]NMDR receptors[blank_end] in the [blank_start]brainstem[blank_end] causes low activity of [blank_start]glutamate[blank_end] in connected pathways, causing high activity in the [blank_start]mesolimbic pathway[blank_end] and low activity in the [blank_start]mesocortical pathways[blank_end].

Therapy - Antipsychotics • Note that DA [blank_start]agonists[blank_end] (e.g. methamphetamine) can produce behavioural phenomenon indistinguishable from acute schizophrenia, so this supports the dopamine [blank_start]overactivity[blank_end] hypothesis • Nearly all antipsychotics are [blank_start]D2 antagonists[blank_end] but some also block [blank_start]5-HT2A[blank_end] to varying degrees • Potency correlates with [blank_start]activity[blank_end] at D2 receptors - not but dose [blank_start]not[blank_end] correlate effectiveness. • “Typicals” are [blank_start]less[blank_end] effective at treating [blank_start]negative[blank_end] symptoms vs “atypicals” • Days/weeks/months to work suggests [blank_start]secondary[blank_end] effects e.g. [blank_start]↑ D2 receptors in limbic structures[blank_end]

“Typical” antipsychotics – D2 antagonists - and how they affect the dopaminergic pathways: 1. Mesolimbic - reduces to [blank_start]normal[blank_end] activity, stopping positive symptoms and the [blank_start]pleasure/reward[blank_end] response. 2. Mesocortical - still low activity 3. Nigrostriatal - reduced to [blank_start]low[blank_end] activity, explains [blank_start]parkinsonian[blank_end] side effects 4. Tuberoinfundibular - [blank_start]reduced[blank_end] to low activity, explains elevated [blank_start]prolactin[blank_end]

‘Typicals’ aka ‘First generation antipsychotic’ side effects: - Extrapyramidal side effects – direct block of nigrostriatal DA receptors • [blank_start]Dystonia[blank_end] - Muscle spasm within hours, can be fatal • [blank_start]Akathisia[blank_end] - subjective tension & need to move, objective restlessness, distress • Pseudo-Parkinsonism - [blank_start]rigidity, tremor, bradykinesia,[blank_end] gait disturbance • Tardive Dyskinesia - [blank_start]abnormal involuntary[blank_end] movements, reversible? - Dry [blank_start]mouth[blank_end], blurred [blank_start]vision[blank_end], constipation, weight [blank_start]gain[blank_end], sedative, [blank_start]QT[blank_end]-prolongation, dyscrasia’s, postural [blank_start]hypotension[blank_end], elevated prolactin - Sexual [blank_start]dysfunction[blank_end] common with both typical and ‘atypicals’ Role in current treatment - history of [blank_start]good[blank_end] response, [blank_start]range[blank_end] of depots, good for [blank_start]acute[blank_end] management e.g. chlorpromazine, haloperidol, zuclopenthixol, fluphenazine.

“Atypical” antipsychotics • D2 antagonists AND [blank_start]5-HT2A antagonism[blank_end] - defining property of ‘atypicals’ • Critically, [blank_start]less[blank_end] likely to induce dystonia/akathisia/[blank_start]Parkinsonism[blank_end] in the antipsychotic naïve • Reduced [blank_start]negative[blank_end] symptoms in contrast to the ‘typicals’- debatable? • Perceived side effects [blank_start]less common[blank_end] with atypicals? e.g. olanzapine, risperidone etc. • Metabolic syndrome - weight [blank_start]gain[blank_end], elevated [blank_start]lipids[blank_end], insulin [blank_start]resistance[blank_end], diabetes • Less effect on prolactin - except [blank_start]risperidone[blank_end] • ~ 30-50% of all patients are treatment-resistant to varying degrees and need [blank_start]clozapine[blank_end]

Antipsychotic antagonism of WHICH RECEPTORS is associated with weight gain?

Antipsychotic M3 antagonism impairs:

Which of these drugs is MOST likely to cause hypotension?

Which 2 drugs are the most sedating?

Which 3 drugs are most likely to cause extra-pyrimidal SEs?

Treatment resistant schizophrenia • Defined by - treatment with a minimum of [blank_start]2[blank_end] antipsychotics for at least [blank_start]6[blank_end] weeks at maximum [blank_start]tolerated[blank_end] dose • Occurs in ~[blank_start]30[blank_end]% of patients with schizophrenia • Clozapine induces remission in ~[blank_start]30-50[blank_end]% of patients with TRS, and is the only antipsychotic shown to decrease [blank_start]suicide & re-hospitalization[blank_end] rates, and increase rate of [blank_start]independent[blank_end] living • Takes about 9 [blank_start]years[blank_end] on average post-first-psychotic-episode before used in NZ due to significant side effects - during this time patients typically have very poor quality of life

Which of these is NOT a side effect of clozapine?

Clozapine monitoring: - Verbal for [blank_start]constipation[blank_end] - toxic megacolon risk - Blood monitoring for [blank_start]agranulocytosis[blank_end] (0.8% of patients, during the first year peaks at 8-10 weeks of Tx) and [blank_start]neutropenia[blank_end] (3-4%) • Monitor [blank_start]weekly[blank_end] for the first 18 weeks, then every 2 weeks for the remainder of the year, then [blank_start]monthly[blank_end] • 2.4 fold higher incidence in [blank_start]Asians[blank_end] versus caucasians with a 5% increase in risk/decade • [blank_start]38[blank_end]% experience a further issue following re-challenge after neutropenia... • NO re-challenge following [blank_start]agranulocytosis or myocarditis[blank_end]

Clozapine Interactions • Metabolised by CYP450 1A2 and less so by 2D6) – levels decreased by high levels of [blank_start]caffeine, valproate, carbamazepine[blank_end], cigarette smoking - levels increased by [blank_start]clarithromycin, rifampicin, erythromycin[blank_end], [blank_start]fluoxetine, paroxetine[blank_end] • [blank_start]Benzodiazepines[blank_end] may increase sedation and respiratory depression • [blank_start]Anticholinergics[blank_end] may increase constipation risk, pyrexia • Evening [blank_start]primrose[blank_end] oil and [blank_start]tramadol[blank_end] may increase seizures • [blank_start]Lithium[blank_end] may exacerbate ADRs