Psychosis - Special Populations

What is the mesolimbic pathway?

• anatomy → projections from VTA to nucleus accumbens

• physiology → motivation, emotions, rewards, positive symptoms of schizophrenia

• implications → D2 antagonist reduce positive symptoms of schizophrenia

What is the mesocortical pathway?

• anatomy → projections from the VTA to the prefrontal cortex

• physiology → cognition and executive functions, emotions and affect

• implications → hypofunction might be related to cognitive and negative symptoms in schizophrenia 

What is the nigrostriatal pathway?

• anatomy → projections from the substantia nigra to striatum (caudate/putamen)

• physiology → stimulation of purposeful movement

• implications → D2 antagonism induces EPS 

What is the tuberoinfundibular pathway? 

• anatomy → hypothalamus to infundibular region of median eminence

• physiology → DA released into portal circulation connecting median eminence with anterior pituitary gland, which tonically inhibits prolactin release 

• implications → D2 antagonism increases prolactin levels, by disinhibition 

What are the sex-based differences of average age of onset for schizophrenia?

• males → early 20s

• females → mid-late 20s + second peak at 45-49y 

Why are there sex-based differences in schizophrenia diagnosis?

• males

  • more likely to have SUD (cannabis, cocaine, methamphetamine)

  • more likely to also have autism-spectrum disorder

• females

  • less severe positive and negative symptoms 

  • more anxiety disorders, eating disorders, personality disorders, PTSD, suicide attempts and self-injurious behaviours 

  • more likely to get diagnosed with a mood disorder before diagnosis of schizophrenia (misdiagnosis)

How does the presentation of schizophrenia differ between sexes?

• incidence 1.4x males > females

• females better:

  • antipsychotic response

  • QoL

  • social supports

  • employment

• males more:

  • hospitalizations 

  • brain abnormalities 

What are good prognostic features for schizophrenia?

• abrupt/acute onset 

• later onset 

• presence of precipitating factor 

• good premorbid personability 

• paranoid and catatonic subtypes 

• short duration < 6 months 

• predominance of positive symptoms 

• family history of mood disorders

• good social support 

• female

• married 

• out-patient treatment 

What are poor prognostic features for schizophrenia?

• insidious onset

• younger onset

• absence of precipitating factors 

• poor premorbid personality 

• simple, undifferentiated subtypes 

• long duration > 2 years 

• predominance negative symptoms 

• family history of schizophrenia 

• poor social support 

• male

• single, divorced, or widowed 

• institutionalized 

What is the estrogen hypothesis in schizophrenia?

• estrogen may have neuroprotective effects

  • genetic variants of estrogen-receptor-alpha associated with schizophrenia and worse symptoms

• estrogen impacts DA

  • via inhibition of COMT → less breakdown of DA

  • by increase sensitivity of D2/3 autoreceptors in mesolimbic region → inhibit DA neuron firing, reduce DA synthesis and release (less positive symptoms)

  • by increase sensitivity of postsynaptic DA receptors in cortical region (less negative symptoms)

How does estrogen impact antipsychotics?

• increase sensitivity of D2/3 receptors means lower doses needed

• estrogens can alter activity of certain CYP enzymes

  • meaning dose adjustments required during pregnancy or with oral contraceptives

Which enzymes have increased activity in females?

• 2A6

• 2B6

• 2D6 → haloperidol, risperidone, aripiprazole, brexpiprazole

• 3A4 → quetiapine, aripiprazole, brexpiprazole, haloperidol, lurasidone, cariprazine 

*with further increased activity during pregnancy, potentially even lower doses 

Which enzymes have decreased activity in females?

• 1A2 → clozapine, olanzapine 

*with further suppression of activity during pregnancy, potentially even lower doses 

What is the effect of prolactin on estrogen?

• estrogen directly stimulates synthesis and secretion of prolactin 

• where hyperprolactinemia

  • feedback loop to inhibit GnRH → inhibit LH/FSH → reduce estrogen → less neuroprotective effects 

*want to select an antipsychotic that has less risk of hyperprolactinemia 

What is the risk of hyperprolactinemia in antipsychotics?

• minimal to no risk

  • aripiprazole

  • brexpiprazole

• low risk 

  • quetiapine (minimal to low) 

  • asenapine 

  • clozapine 

  • ziprasidone 

• moderate risk 

  • lurasidone

  • olanzapine 

• high risk 

  • haloperidol

  • risperidone/paliperidone 

Is there evidence for supplemental estrogen in females with schizophrenia?

• as adjunctive treatment saw some improvement 

  • significant when > 200mcg, but NOT with 100mch 

• when using a triphasic estrogen adjunct, it did not prevent relapse

• improved negative symptoms in postmenopausal schizophrenia 

• overall: most psychiatrists won’t use estrogen, only specialists will and even typically if seen symptom worsening with menses 

What is the incidence and onset of postpartum psychosis?

• 1/500-1000 births

• typically seen within first 2 weeks

  • with more than half occurring in first 3 days

What are the symptoms seen with postpartum depression?

• odd affect

• withdrawn 

• distracted by auditory hallucinations

• incompetent 

• confused 

• catatonic

• elated

• labile

• rambling

• agitated

• excessively active 

*often described as “kaleidoscopic” - symptoms all over the place and varying across patients 

What are the risk factors of postpartum psychosis?

• non-modifiable 

  • precipitous fall in estrogen and progesterone (losing protective factor) 

  • history of postpartum psychosis in first degree relative

• modifiable 

  • sleep loss/circadian rhythym changes

  • abrupt cessation of breastfeeding (disruption of hormones)

  • use of antidepressants, due to risk of manic switch 

Is there an underlying cause of postpartum psychosis?

• highly suggestive of bipolar 1 disorder 

  • hormone drop as a trigger 

  • primiparity risk factor for first episode bipolar 

What are the risks of postpartum psychosis?

• maternal suicide and/or infanticide

  • rare but significantly increased w/i first year 

What is the treatment for postpartum psychosis?

• no approved medications specific for this indication

• lack of standardized treatment, recommendations: 

  • admission to hospital, preferrable mother/baby unit with close monitoring from psychiatry 

  • start treatment with antipsychotic ± mood stabilizer ± benzodiazepines and if severe ECT (consider if breastfeeding) 

Can estrogen be initiated for postpartum psychosis?

• Estrogen should not be used within the initial 6-12 postpartum 

  • postpartum females are hypercoagulable, and adding estrogen increases clot risk even further 

  • if breastfeeding, estrogen can lower milk production 

What is late onset psychosis?

• When the first episode of psychosis develops after the age of 40

• common types or scenarios where see late onset psychosis:

  • late onset schizophrenia (LOS)

  • delusional disorder

  • psychotic depression

  • psychosis in Parkinson’s Disease

  • psychosis in delirium 

  • psychosis in major neurocognitive disorders (Alzheimer’s & LBD) 

  • other secondary psychoses 

What is the incidence of LOS? 

• ~20% schizophrenia patients developed their symptoms after the age of 40y 

What are the 2 groups of late-onset schizophrenia?

• LOS → onset between 40-60

• Very-late-onset schizophrenia like psychosis(VLOSLP) → onset after 60; believed the psychosis in this population is due to neurodegenerative causes 

What are the main symptoms/prognosis differences between LOS and EOS? 

• LOS have better prognosis: 

  • less positive symptoms 

  • less disorganized thinking 

  • require lower dose antipsychotics 

  • better premorbid functioning 

• LOS have more: 

  • persecutory delusions (paranoia where believe they are being harmed)

  • delusions of reference (where believe ordinary/unrelated events have significance to them personally)

  • person/running commentary auditory hallucinations

What is the relationship between schizophrenia and dementia?

• if EOS

  • 2.1x increased risk of dementia 

  • 70% vs 11% once 80y to have dementia 

• if LOS 

  • LOS - not associated with increased risk 

  • VLOSLP - very common, but symptoms are likely secondary to neurocognitive disorder in the first place 

What PK differences in older adults that have LOS do you need to consider when trying to decide treatment?

• increased volume of distribution 

• slower elimination 

• decreased circulating proteins 

• increased BBB permeability 

• decreased autonomic responses 

*increases patients risk for ADEs, including ESP, hypotension, falls, anticholinergic effects and metabolic syndrome 

Due to the difference in PK in patients with LOS, does this change dosing? 

• evidence shows that reduction of 40% dose following acute management does NOT increase risk of relapse in LOS 

*NOTE: this is NOT the same as in EOS patients that are now older, where higher doses may be required for stability.

What is delusional disorder?

• where patients have prominent delusions without hallucinations 

  • delusions = fixed false belief which is based on inaccurate interpretation despite evidence to the contrary 

  • can understand that others do not believe then, but cannot accept their beliefs are wrong

What is the onset and prevalence of delusional disorder?

• onset middle to late age 

• 0.03% in older adults 

What is the diagnostic criteria for delusional disorder?

• 1+ delusion for > 1 month 

• does not meet criteria A of schizophrenia (5+ symptoms)

• apart from impact of delusions, function not markedly impaired 

• any manic or depression episodes must be brief in comparison to delusional episode 

• bizarre vs non-bizarre 

  • does not change treatment 

  • some experts believe diagnosis should only include non-bizarre beliefs 

• consideration of cultural and religious beliefs accounted for 

  • e.g. “God touched me” may be different in religious vs non-religious person 

What are risk factors for delusional disorder?

• non-modifiable

  • family history of schizophrenia or cluster A personality disorders 

  • brain abnormalities in frontal or temporal lobe, or basal ganglia 

  • sensory impairment (visual or hearing loss) 

  • old age 

• modifiable 

  • linguistic barriers, like diglossia (different language at home vs work) 

  • widowed women or celibacy in men 

  • social isolation 

  • personality factors (hypersensitivity, suspicion, narcissistic traits and low self-esteem) 

What are the different subtypes of delusional disorders?

• erotomanic → another person is in love with the patient 

• grandiose → patient have a great but unrecognized talent, insight or discovery

• jealous → their lover is unfaithful (aka Othello syndrome)

• persecutory → patient is being conspired against, cheated, spied upon, poisoned (most common) 

• somatic → involves bodily functions or sensations 

• mixed 

• unspecified 

How is delusional disorder treated?

• extremely difficult to treat → only 1/3 respond to antipsychotics 

  • some evidence that FGA more efficacious 

  • pimozide believed to be of benefit, but no evidence of superiority 

• employment/volunteering improves symptoms 

*improvement is often a lessening of impact of delusions not removal/resolution 

What is psychotic depression? 

A subtype of major depressive disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations, often related to the individual’s depressive themes. Delusions more common than hallucinations, but derogatory and belittling auditory hallucinations may exist. 

What is the prevalence and onset of psychotic depression?

• lifetime prevalence of 0.35%

• average age of onset 50y 

  • if late age, typically unipolar depression 

  • if young, typically bipolar depresion 

What are the common symptoms of psychotic depression?

• common symptoms of depression but more severe, persistent and recurring 

  • worse cognitive symptoms (except verbal fluency is similar) 

  • higher rate of suicide 

• delusions of guilt → patient responsible for a horrible event 

• worthlessness

• nihilism → life has no meaning 

• somatic delusions (headaches, GI upset w/ no biological cause) 

• psychomotor retardation 

• delusions/hallucinations

How is psychotic depression treated?

• combo antidepressant and antipsychotic

  • more effective than either monotherapy

  • no specific guidelines, so use treatment resistant depression recommendations

• if non-responsive, ECT more effective

What is the incidence of psychosis in Parkinson’s Disease?

• about 60% of PD patients will experience psychosis over the lifetime of their illness

  • longer duration of illness, higher the risk

What is the potential causes of psychosis in PD?

• increased DA from medications used to treat motor symptoms (most common hypothesis) 

• associations between hallucinations in PD and REM sleep behaviour dysfunction that is commonly see in LBD 

*note: some medication naive patients experience minor hallucinations

What type of psychosis is most commonly seen in PD?

• hallucinations most common symptoms

  • particularly visual 

  • medication naive may experience passage or presence hallucinations 

• delusions may exist 

  • most commonly jealous or paranoid type

How is psychosis treated in PD?

• lower dose of DA agents

  • balance between worsening PD psychomotor symptoms and psychosis

  • d/c in order of: anticholinergice, amantadine, MAOBi, DA, COMT, levodopa 

• add quetiapine 

  • lowest rates of EPS, but not good evidence for efficacy 

• pimavanserin (not in Canada) 

  • inverse agonist 5-HT2A/C 

What is transcultural psychiatry?

Transcultural psychiatry is the study of how cultural factors influence mental health, diagnosis, and treatment across different populations. It emphasizes understanding the cultural context of psychiatric symptoms and the therapeutic relationship.

True or False: There is no difference in risk of psychosis across ethnicities. 

False.

What is the difference in risk for a diagnosis of psychosis in Black Americans vs White Americans? 

Black Americans 3-4x more likely to be diagnosed. 

Why might migrants or certain ethnic minorities have a higher risk for a diagnosis of psychosis? 

• racism can play a large role 

• material and social deprivation 

• childhood adversity 

• marginalization and discrimination 

• diagnostic bias 

  • evidence supports psychosis diagnosis as a means to exert social control 

  • conflate though who do not conform as deviant/mentally ill

  • diagnostic tools not culturally adapted/validated in non-white people (most literature stems from US and UK)

*biological causes have been completely discredited for the increase indifference b/w ethnic groups/races 

What did the study by Luhrmann et al show about auditory hallucinations across different cultures? 

• USA → hallucinations more violent, commanding voices to harm someone/themselves; not single person said they were good voices

• India → half said voices were family members, providing guidance or scolding, and commands were or domestic tasks; if was distressing was when voices talked about sex

• Ghana → almost all described hearing voice of God, half said voice was good and even if some bad the good outweighed; few heard violent commanding voices, but more committed violent acts

What did the review from Ghanem et all show us about different types of hallucinations/delusions in different countries?

• auditory most frequent experienced by all ethnic groups 

• EU > gustatory or olfactory hallucinations 

• West African > visual hallucinations vs EU 

• within Britain

  • white → > violent auditory and delusions of reference 

  • Pakistani-British → > persecutory delusions 

What is the evidence of Indigenous peoples and psychosis? 

• most research coming out of Australia/New Zealand, but direct investigations still lacking 

• in MB, Indigenous children 4.4x higher rate of being diagnosed with schizophrenia vs other Manitobans 

• current research overemphasizes suicide and problematic substance use

What are some of the risk factors that might impact Indigenous peoples to have higher rates of psychosis?

• generational trauma

• racism (even subconsiously)

• increase SUD (7x higher than general population - typically tied to past trauma)

• lower social determinants of health linked to increase rates psychosis

  • low income, lack of access to clean water, etc.

• discrimination leading to over-diagnosis 

How can meth use specifically lead to psychosis?

• With persistent use can cause damage to brain in the same area that causes schizophrenia

  • even once remove the meth use, if it was used for long enough there is still persistent psychosis