Schizophrenia:
~ ❌ % of population, psychotic illness, mostly ❌ people, ❌ (regular/irregular psychotic episodes), lifelong and highly disabling.

Positive and negative symptoms:
- A positive symptom is one that ❌ a behavior, thought or feeling. Positive symptoms associated with schizophrenia also occur in other disorders such as ❌, psychotic depression, and ❌'s. Positive symptoms are – ❌ (paranoid), hallucinations, thought ❌, other abnormal behaviors e.g. aggression.
- Negative symptoms ❌ a behavior, thought or feeling. Negative symptoms – flattened ❌ response, social ❌, apathy, anhedonia.

Cognitive symptoms:
- ❌ - poor methodical planning in brain makes basic tasks difficult
- Difficulty representing and maintaining ❌, allocating ❌, evaluating/monitoring performance
- Impaired ❌ fluency
These are the best predictor of outcome.

Burden of illness
• 25-50% attempt suicide and ❌% eventually succeed
• Mortality rate 8 times higher than general population due to high rate of ❌ etc,
• Life expectancy ❌ years shorter than the general population
• Patients - early onset, intellectual ❌, relationships, risk of suicide, stigma, self treatment: ❌
• Family/Care Giver - stressors, financial ❌, pressure on ❌
• Community – healthcare, economic, stigma
• Duration of ❌ (DUP) has major impact on outcomes

Early symptoms indicating the onset of schizophrenia:
• Worrisome drop in ❌
• New trouble ❌
• Suspiciousness, ❌ ideas or uneasiness with others
• Withdrawing socially, spending a lot more time ❌ than usual
• Unusual, overly intense new ❌, strange feelings or having ❌ feelings at all
• Decline in ❌
• Difficulty telling reality from fantasy
• Confused ❌ or trouble communicating

Match the symptoms to the region:
Positive symptoms - ❌
Affective symptoms (anxiety, suicidality) - ❌
Aggressive symptoms - ❌
Cognitive symptoms - ❌
Negative symptoms - ❌

Diagnosis
• Based on patient and often family ❌ following presentation of first psychotic episode
• Clinical status/rating determined using psychiatric examination with ❌ (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)
• ❌ not otherwise specified often in patient notes due to ❌ associated with the term schizophrenia

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

Schizophrenia - the ❌ Dopamine Hypothesis.
Majority of symptoms explained by dysregulation of dopaminergic pathways:
- ❌ activity of mesolimbic pathway explains pos symptoms
- ❌ activity of mesocortical pathways explains cog, aff, neg symptoms
- ❌ 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. ❌
2. ❌
3. ❌
4. ❌

NMDA receptor hypofunction hypothesis:

There are NMDA receptors in the brain. NMDA receptors in the ❌ have glutamate projections. A glutamate projection is a ❌ pathway that uses glutamate, an ❌ neurotransmitter. Schizophrenia may be caused by ❌ activity in these glutamate projections.
When the glutamate projections are ❌-active, downstream ❌ of the mesolimbic DA pathway does ❌ occur, meaning the ❌ DA pathway is ❌. This causes positive symptoms.
Also low ❌ of the excitatory NT glutamate means ❌, and ❌ DA pathways become ❌. This may cause the cognitive, negative, and affective symptoms.

TLDR; Low activity of ❌ in the ❌ causes low activity of ❌ in connected pathways, causing high activity in the ❌ and low activity in the ❌.

Therapy - Antipsychotics
• Note that DA ❌ (e.g. methamphetamine) can produce behavioural phenomenon indistinguishable from acute schizophrenia, so this supports the dopamine ❌ hypothesis
• Nearly all antipsychotics are ❌ but some also block ❌ to varying degrees
• Potency correlates with ❌ at D2 receptors - not but dose ❌ correlate effectiveness.
• “Typicals” are ❌ effective at treating ❌ symptoms vs “atypicals”
• Days/weeks/months to work suggests ❌ effects e.g. ❌

“Typical” antipsychotics – D2 antagonists - and how they affect the dopaminergic pathways:
1. Mesolimbic - reduces to ❌ activity, stopping positive symptoms and the ❌ response.
2. Mesocortical - still low activity
3. Nigrostriatal - reduced to ❌ activity, explains ❌ side effects
4. Tuberoinfundibular - ❌ to low activity, explains elevated ❌

‘Typicals’ aka ‘First generation antipsychotic’ side effects:
- Extrapyramidal side effects – direct block of nigrostriatal DA receptors
• ❌ - Muscle spasm within hours, can be fatal
• ❌ - subjective tension & need to move, objective restlessness, distress
• Pseudo-Parkinsonism - ❌ gait disturbance
• Tardive Dyskinesia - ❌ movements, reversible?
- Dry ❌, blurred ❌, constipation, weight ❌, sedative, ❌-prolongation, dyscrasia’s, postural ❌, elevated prolactin
- Sexual ❌ common with both typical and ‘atypicals’

Role in current treatment - history of ❌ response, ❌ of depots, good for ❌ management e.g. chlorpromazine, haloperidol, zuclopenthixol, fluphenazine.

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

Treatment resistant schizophrenia
• Defined by - treatment with a minimum of ❌ antipsychotics for at least ❌ weeks at maximum ❌ dose
• Occurs in ~❌% of patients with schizophrenia
• Clozapine induces remission in ~❌% of patients with TRS, and is the only antipsychotic shown to decrease ❌ rates, and increase rate of ❌ living
• Takes about 9 ❌ 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

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

Clozapine Interactions
• Metabolised by CYP450 1A2 and less so by 2D6)
– levels decreased by high levels of ❌, cigarette smoking
- levels increased by ❌, ❌
• ❌ may increase sedation and respiratory depression
• ❌ may increase constipation risk, pyrexia
• Evening ❌ oil and ❌ may increase seizures
• ❌ may exacerbate ADRs