Module 16: Psychotic Disorders and SZ (1)

Psychosis

• A collection of symptoms that can form part of a disease

• It is an abnormality of the mind and can involve:

  • Delusions e.g. thoughts of persecution

  • Hallucinations – seeing/hearing/feeling/smelling things that aren’t there

  • Disordered thoughts

  • Catatonia

Active Psychosis

• A highly disabling condition

• It is more disabling than blindness and paraplegia, but less so than dementia and quadriplegia

Causes of Psychosis

• It can occur as part of various conditions and external factors:

• Mental health conditions:

  • Affective disorders (e.g., Bipolar Disorder, Major Depressive Disorder) – with psychotic specifiers

  • Anxiety disorders – e.g., PTSD

  • Alzheimer’s Disease and other neurodegenerative conditions

• Non-illness-related causes:

  • Illegal drugs (e.g., stimulants, hallucinogens)

  • Prescription medications

  • Sleep deprivation

  • Caffeine intoxication

First Episode Psychosis

• Often occurs unexpectedly and can't be immediately linked to a specific mental health condition.

• A person may be diagnosed with Brief Psychotic Disorder, which is:

  • A period of psychosis not caused by conditions like schizophrenia, BPD, or MDD.

• A more definitive diagnosis typically comes later, once the condition develops further.

Prodromal Phase

• The period before acute psychosis, marked by behavioural changes such as:

  • Irritability, difficulty concentrating, memory issues

  • Anxiety and depression

• This phase can last months or years and is often hard to recognise, especially if symptoms mimic other mental health disorders (e.g., depression).

Importance of Early Intervention For Psychosis

• Delays in treatment are common because:

  • The person may not realize they are ill

  • Friends/family might not understand what's happening

• Delayed treatment is linked to worse outcomes

• If psychosis is part of an ongoing/ underlying condition (e.g., schizophrenia), future episodes are likely

  • Recognising prodromal symptoms can help intervene earlier in future episodes

Diagnosis of Schizophrenia

• Uses the DSM-5 criteria

• Two or more of the following symptoms must be present for at least 1 month, and one must be a positive symptom (1–3 below):

  1. Hallucinations

  2. Delusions

  3. Disorganized speech

  4. Disorganized or catatonic behavior

  5. Negative symptoms

• There must be significant impairment in functioning.

• Continuous signs of disturbance in behaviour must be present for 6+ months.

• Symptoms must not be better explained by another condition.

• ICD-10 diagnostic criteria are similar to DSM-5.

Positive Symptoms of Schizophrenia

• Symptoms are behaviours or experiences added/ in addition to normal functioning.

• Heavily emphasised in DSM-5.

• Include:

  • Hallucinations (e.g., hearing voices)

  • Delusions (false beliefs)

  • Disorganised speech

  • Disorganised or catatonic behaviour

• These are not present in healthy individuals, hence considered “positive.”

Negative Symptoms of SZ

• Symptoms are behaviours or responses that a person with SZ has that normal individuals doesn’t have → represents deficits in normal emotional or behavioural functions:

  • Flat affect (loss of emotional expression)

  • Anhedonia (inability to feel pleasure)

  • Apathy (lack of motivation or interest)

Cognitive Symptoms of SZ

• Include:

  • Difficulty processing information

  • Impaired attention or memory

Schizoaffective Disorder

• A hybrid of SZ with a mood disorder (BPD and MDD)

• Meets criteria for schizophrenia AND there is also a major mood episode (mania or depression)

  • manic and depressive episodes: SZA with bipolar type

  • depressive only: depressive type

  • mixed (manic and depressed simultaneously)

Name Some Features of Schizoaffective Disorder (Katie 35 y/o Female Case Study)

• Suffered psychotic symptoms for 8 years previously. Usually very well controlled.

  • Relapsed and began experiencing hallucinations

  • Voices: constant commentary on actions, life choices

  • Tactile hallucinations

  • Visual hallucinations

  • Delusions that food was being poisoned -> anorexia

  • Delusions that husband was conspiring with family

  • Delusions that people were trying to harm her son

  • These symptoms are characteristic of SZ

  • Mania: high level of activity directed at delusions

  • Social withdrawal culminating in virtual catatonia

  • Sectioned 4 times in 3-year period.

Epidemiology of Schizophrenia

• Common - Around 1% of the population

• Males 1.4x female – more common in males

• Strikes at an early age

  • Males: late teens

  • Females: late twenties; second peak at menopause

• Highly disabling – causes major disability with no cure

Myths Vs Facts of SZ

• Myth: People with schizophrenia have split personalities.
  ➤ Fact: This confuses SZ with dissociative identity disorder. "Schizo" refers to a split from reality, not identity.

• Myth: People with schizophrenia are dangerous.
  ➤ Fact: Most are not dangerous to others. A small minority may show violence, but they’re more likely to harm themselves (e.g., high suicide risk).

• Myth: People with schizophrenia will never recover.
  ➤ Fact: Many experience partial or full recovery and can lead productive lives with appropriate treatment.

Additional Clinical Features of SZ

• Psychiatrists may look for associated symptoms:

  • Sleep disturbances

  • Anxiety

  • Cognitive difficulties

• These don't form part of the core diagnostic criteria but may support the diagnosis.

• Neurological soft signs may also be present:

  • Motor abnormalities

  • Difficulty distinguishing right from left

  • Other subtle neurological deficits

Schizophrenia and Suicide

• Higher rate of suicide with SZ rather than depression

• Estimated that ~5% of those with SZ take their own lives – double the rate of those with depression

• BPD type 1 has a higher rate of 10-15%

Patterns of Care: Bedlam (1700s and Earlier)

• Inmates of the bedlam lunatic asylum were subject to terrible conditions with no effective treatment → were treated as entertainers for wealthy visitors

Patterns of Care: Joint Counties Asylum - Abergavenny (1850)

• Legislations resulted in the building of public lunatic asylums, inspected by government conditions still brutal and more like a prison then a hospital

  • Beginning of a more humanitarian approach – led by the Quaker Tuke Family

Patterns of Care: Norther Michigan Asylum (Late 19th, Early 20th Century)

• Improvement in conditions, with psychiatry recognised as a medical speciality

• Treatments confined to psychical approaches e.g. surgery, ECT, fever therapy and insulin shock

• Hospital ward:  communal wards where SZ were often housed alongside elderly patients with senile dementia – violence between patients was common, with staff having to use physical restraints used

  • Communal wards are still present, but conditions are much better

• Inpatient explosion decline – peak in mental hospital numbers occurred in the US with 6 in 1000 adults being inmates in an institution

  • Decline in numbers in 1955 following the introduction of the first antipsychotic, Thorazine

Patterns of Care: Norther Michigan Asylum: 1970s onwards

• Many older psychiatric hospitals like Barrow Hospital were closed

• Emphasis moved from institutional care to care in the community

• Unity centre provided ‘hall of residence’ style facilities rather than traditional psych hospitals

• Today few people are residents in psychiatric hospitals

• Some people do need residential care to either protect them from themselves or to protect society

• Mental Health Act legislation allows people to be detained in psychiatric hospitals against their will

Mental Health Act 1983

• "Sectioning" refers to legal detention of an individual under this act

• Allows compulsory hospitalisation and treatment for individuals with serious mental health conditions.

• Used only if the person is a danger to themselves or others.

• Includes safeguards and legal checks to prevent its misuse and abuse

• Powers granted to medical professionals, social workers, and police.

Section 2 and Section 3 of the Mental Health Act 1983

• Section 2: 28-day assessment and treatment order.

• Section 3: 6-month treatment order (can be renewed).

  • Typically used for ongoing mental illness where a diagnosis already exists.

Sectioning

• Application to ‘detain an individual’ is made by a near relative or “approved mental health professional”

• The patient must be seen by two doctors (one must be a psychiatrist) and an Approved Mental Health Professional

• Cannot refuse treatment (except ECT)

• Used in SZ, MDD, and BPD where an individual is a danger to themselves or others

Risk Factors for Schizophrenia

• Its origin is unknown but both genetics and environmental and social factors can increase an individual risk

• Environmental and social factors can cause epigenetic changes → early child hood trauma can causes changes in the HPA axis which can increase the risk of mood disorders in later life

Schizophrenia: Genetic Risk Factors

• Rate of 1% in the general population

• The rate increases to 8-10% if near relative affected

• A concordance rate of 50% in twin studies

  • unlikely a single gene, probably many “tendency” genes that have a small impact individually but collectively more profound

    • e.g. DISC1

  • tendency genes may require environmental impact too

Schizophrenia: Environmental Risk Factors

• Winter birth (controversial risk factor – myth?)

  • May be maternal exposure to viruses

• Substance abuse may be involved

  • amphetamine -> psychosis and worsen psychosis in SZ/ cause relapse

  • cannabis? increases risk

  • BUT schizophrenics have a high risk for substance abuse (cause or effect?)

AKT1

• A gene that codes for a kinase that inactivates glycogen synthase kinase (GSK).

• GSK is implicated in BPD and is a target of lithium treatment.

• GSK also plays a role in dopamine (D2) receptor signaling, linking it to SZ (schizophrenia).

• This suggests AKT1 impacts dopamine-related pathways, relevant to both BPD and SZ.

How does AKT1 genotype influence schizophrenia (SZ) risk with cannabis use

• A study used odds ratios to assess SZ risk in different AKT1 genotypes:

  • T/T (Homozygous wild-type): No increased SZ risk, regardless of cannabis use.

  • C/T (Heterozygous): Also no change in SZ risk.

  • C/C (Homozygous mutant): Heavy cannabis users had a 7-fold increased risk of SZ.

• Shows genetic risk (AKT1) interacts with environmental factors (cannabis) in SZ development.

Schizophrenia: Social Risk Factors:

• Difficult childhood conditions can increase risk

  • discrimination

  • dysfunctional families

  • abuse/trauma

• Epigenetic changes? – likely affects different genes to those in BPD or MDD

Schizophrenia As A Neurodevelopmental Disorder

• Question as to whether SZ is a neurodevelopmental or neurodegenerative disorder

• Age of onset (teenage/early adult) – favours neurodevelopmental hypothesis – a time when the brain undergoes a series of changes

• Structural differences in the brain for those with/w/o SZ

  • Or: a neurodegenerative disorder?

• Progression of disease in many cases, if not treated early

• Reductions in brain volume → the role of Excitotoxicity?

  • The potential influence of glutamate

Schizophrenia: Other Risk Factors

• Infection with T. gondii is a potential risk factor for SZ and BPD.

• The parasite uses cats as definitive hosts and any warm-blooded animal (including humans) as secondary hosts.

• Around 30% of the global population is estimated to be infected.

• It forms cysts in tissues, including the brain, where it can persist for life.

• In rodents, it alters behaviour to make them more likely to be eaten by cats.

• It's suggested that T. gondii may also influence human behaviour, potentially contributing to psychiatric disorders.

Schizophrenia: Dopamine Hypothesis

• It suggests hyperactivity of the mesolimbic pathway (from VTA to ventral striatum) may contribute to schizophrenia.

• Not the root cause, but a final common pathway where multiple factors converge to produce positive symptoms(hallucinations, delusions).

• Evidence supporting the hypothesis:

  • Reserpine (hypertensive drug) depletes dopamine, and when given to SZ patients, it reduces positive symptoms.

  • Amphetamines, which release dopamine, can induce psychosis, which can be treated by SZ medications.

  • L-DOPA and dopamine agonists (Parkinson's treatments) can cause psychosis at high doses.

  • Altered dopaminergic activity (hyperactivity) in certain brain areas may play a role in SZ.

Dopamine Receptors

• 5 subtypes that can be divided into 2 groups

  • D1-Like

  • D2-Like → implicated in SZ

Why Are D2 Receptors the Prime Target for Antipsychotics

• Studies have shown that there is a 1:1 ratio between the therapeutic concentration of antipsychotics (neuroleptics) and the concentration required to occupy 75% of DA D2 receptors.

• This suggests that activity at D2 receptors is crucial for the anti-psychotic activity of these drugs.

4 Dopaminergic Pathways

• Mesocortical pathway from the VTA to the cortex

  • Involved in emotion, fear, motivation.

• Nigrostriatal pathway: substantia nigra to the basal ganglia and into the striatum

  • Emotion, motivation, cognitive control

• Tuberoinfundibular pathway: hypothalamus to the pituitary gland

  • hormone release from pituitary

• Mesolimbic pathway: VTA to the ventral striatum/ nucleus accumbens

  • motor control

Dopamine Pathways in SZ (Traditional View)

• Mesolimbic pathway (VTA → Ventral Striatum): Increased DA transmission here is thought to explain positive symptoms (e.g., hallucinations, delusions) in schizophrenia.

• Mesocortical pathway: Decreased DA transmission here is thought to explain negative symptoms (e.g., anhedonia, apathy) and cognitive problems.

• Tuberhypophyseal pathway: Involved in hormone release from the pituitary, contributing to side effects.

• Nigrostriatal pathway: Regulates motor control, and dysfunction here contributes to Parkinson's disease and motor side effects of antipsychotic medications.

Motor Pathway in Parkinsons (PD)

• Pathway involves a loop:

  • Cortex → Striatum → Globus Pallidus → Thalamus → Cortex.

• The substantia nigra provides input to the striatum, which modulates this pathway.

• This pathway's dysfunction leads to motor symptoms in Parkinson's disease, such as tremors and rigidity.

Cortical Loop of the Reward Pathway

• The loop involved in emotion and motivation (reward pathway) connects:

  • Cortex → Central Striatum (NA, GP) → Thalamus → Cortex.

• The mesolimbic pathway (from the VTA to the ventral striatum) modulates this loop, influencing emotional responses.

• The early dopamine hypothesis suggested that increased DA transmission in the mesolimbic pathway contributes to positive symptoms of schizophrenia (e.g., hallucinations, delusions).

Associative Pathway

• Pathway connects:

  • Cortex → Striatum → GP → Thalamus → Cortex.

• It is involved in habituation, learning, memory, attention, motivation, emotion, and volition.

• The SN-striatal pathway (input from the substantia nigra to the striatum) plays a critical role in high-level cognitive processes.

Dopaminergic Pathways in Schizophrenia (Modern View)

• Functional imaging shows that increased DA in the mesolimbic pathway (VTA → VS) doesn't occur as previously thought.

• Instead, excess DA activity appears in the nigrostriatal pathway entering the associative striatum, which is likely the explanation for positive symptoms in schizophrenia.

Dopamine Hypothesis (Version 3)

• Associative Striatum (AS): Responsible for assigning salience (importance) to stimuli, e.g., threat level.

• Excess noise in AS dopaminergic signaling:

  • Leads to increased (inappropriate) salience assigned to unimportant stimuli, causing positive symptoms(hallucinations, delusions).

• Cognitive impairments:

  • Hypodopaminergic cortical function possibly driven by excessive AS signaling and striatal hyperdopaminergic activity.

• Negative symptoms:

  • Impaired reward-based learning due to excess noise in AS.

  • Inability to assign importance to rewarding stimuli leads to apathy and anhedonia.

  • May be driven by striatal hyperdopaminergic signaling.

NMDA Receptors and Glutamine in SZ

• Glutamate dysfunction may be the root cause of SZ

• NMDA antagonist e.g. ketamine cause psychosis

  • Positive allosteric modulators of Glutamate receptors may be a therapeutic drug

• AMPAkines (positive allosteric modulates of AMPA receptors) may be a new therapeutic approach (but nothing on the market)

Serotonin Receptors in SZ

• LSD causes psychosis

• -ve symptoms of apathy, and avolition in SZ similar to depression (MDD)?

• Probably not the root cause of SZ but 5HT receptor activity in neuro psychotics may give a better therapeutic profile

Muscarinic Receptors in SZ

• Receptors play a role in cognitive and negative symptoms in SZ.

• Receptor antagonists:

  • Worsen negative & cognitive symptoms (e.g., scopolamine, a non-selective mAChR antagonist, can cause psychosis).

  • Antipsychotics without mAChR activity: Lead to serious movement side effects (e.g., tardive dyskinesia).

  • Antipsychotics with mAChR antagonism: Help avoid movement-related side effects.

• Potential therapeutic approach: Muscarinic agonists may be useful, but better side-effect profiles are given by mAChR antagonists.

• Selective allosteric modulators: Subtype-selective modulators might be a viable treatment option (less conserved compared to orthosteric sites).

• Challenges: Developing drugs targeting the orthosteric (ACh) site is difficult, as this site shows little variation between receptor subtypes.

Dirty Drug

• A drug that has effects at its target site and at off-target effects

Antipsychotics as Dirty Drugs

• They are normally D2 antagonists/ partial agonists, inhibiting D2 receptors

  • Actions at many different receptor types

  • Lack of selectivity gives rise to side effects

• BUT! May also give rise to therapeutic benefit e.g. actions at 5HTR (improves therapeutic profile)

Target of Antipsychotics

• Aim to target the excess DA in the associative striatum

• Consider the mesolimbic pathway and the tuberoinfundibular pathway (& motor branch of the nigrostriatal pathway) → contain DA receptors which may be targeted by the antipsychotics

• Have actions at other pathways in the brain

Common Side Effects of Antipsychotics: Extrapyradmial

• Movement disorders

• Includes:

  • Dystonia (muscle contraction) and tardive dyskinesia (jerking/ writhing movements) – can be permanent (continue after treatment terminated)

  • (Motor striatum D2 receptors interference)

Common Side Effects of Antipsychotics: Galactorrheea

• Inappropriate milk production

  • Tuberhypophyseal D2 receptors inhibit prolactin release

  • Blockage of receptors = hyperprolactinemia = excess milk production

Common Side Effects of Antipsychotics: Cognitive Impairement

• ? D2 inhibition in cortex; effects at other receptors e.g. anti-muscarinic effects

  • May act to worsen the cognitive symptoms

Common Side Effects of Antipsychotics: Sedation

• ? H1 antagonism (like sedating antihistamines) – off-target effects

Common Side Effects of Antipsychotics: Weight Gain

• ? H1 and 5HTR antagonism

• Can lead to diabetes, heart disease etc

Common Side Effects of Antipsychotics: Anti-Muscarinic Effects

• Dry mouth

• Blurred vision

• Memory problems

• Cardiac problems

Problems With Antipsychotics

• Medication increases the risk of diabetes → hyperglycaemia is a known side effect of these drugs

• 2012 study found that 10% of people on antipsychotics had T2DM and 37% were pre-diabetic (at risk of development)      

• Rates here are higher than the general population and there are several explanations for this increased risk

Antipsychotics and Obesity

• Many antipsychotics produce significant increases in BMI due to actions at H1 and 5HT receptors

• Obesity is associated with T2DM, increased BMI is likely to be a large reason for the increased risk of diabetes for those on antipsychotics

Antipsychotic Induced Insulin Release

• Antipsychotics can induce insulin resistance independent of their effects on BMI

• This can occur with drugs that don’t produce marked changes in appetite

• Antipsychotics are thought to cause insulin release by inhibiting a component of the insulin signalling cascade (Akt) and by decreasing the phosphorylation of one of its targets of the insulin receptor kinase activity, insulin receptor substrate 1 (IRS-1)

Direct Effect of Antipsychotics on Beta Cells

• Cause pancreatic beta cell dysfunction in several ways

• By acting on muscarinic dopamine, adrenergic and serotonergic receptors, they can decrease insulin secretion

• They may decrease cellular [ATP], decreasing insulin secretions

• May damage beta cells and induce apoptosis