Schizophrenia (Physiology 2)

Psychotic disorders are conditions characterized by a mental state that is out of touch with reality.

Examples include schizophrenia, schizoaffective disorder (schizophrenia + bipolar disorder), and delusional disorder.

Some depressive and manic illnesses also involve psychotic features.

Early onset: Schizophrenia often develops in late adolescence or early adulthood.

Prevalent: It affects around 1% of the population.

Disabling and chronic: It leads to long-term disability and often requires lifelong care.

Mental state: Out of touch with reality.

Abnormalities in perception, thought, and ideas: Distorted thinking and hallucinations.

Altered behaviour: Profound changes, including bizarre and alienating behaviours.

Prevalence: Affects up to 1% of the population.

Influencing factors: Culture, ethnicity, background, and socioeconomic status can influence diagnosis and understanding.

Urban areas: Schizophrenia is more common in urban environments.

Men: Earlier onset, higher propensity to negative symptoms, lower social functioning, and more co-morbid substance abuse.

Women: Later onset, more affective symptoms.

These differences in progression and symptoms highlight the diverse nature of the disorder.

Late teenage years: Often associated with social isolation, interest in fringe cults, and social withdrawal.

These symptoms may go unnoticed or be misinterpreted as typical adolescent behavior.

The cost of treating schizophrenia is approximately six times higher than the cost of treating heart disease.

Schizophrenia is a chronically disabling condition, with significant impacts on quality of life and morbidity.

Positive

Cognitive

Negative

Hallucinations (e.g., visual, auditory)

Delusions

Disorganized thought/speech

Movement disorders

Impaired working memory

Impaired attention

Impaired comprehension

Social withdrawal

Anhedonia (lack of pleasure)

Lack of motivation

Poverty of speech

Emotional flatness

Two or more symptoms must persist for at least 6 months to be classed as schizophrenia.

Hallucinations are perceptions experienced without a stimulus (functional hallucination).

Most commonly auditory.

Voices talking about them (third person)

Voices talking to them

Voices giving a running commentary

Voices echoing their thoughts (thought echo)

Patients may engage in a dialogue with the voices.

Patients may obey the commands given by the voices.

A fixed/unshakable belief not consistent with cultural/social norms.

Often paranoid, such as the belief that they are under the control of an external influence.

Believing there is a conspiracy to harm them.

Peculiar forms of motility

Stupor

Mutism

Stereotypy (purposeless, repetitive acts)

Mannerism (bizarre postures, strange mannerisms)

Spontaneous automatism (impulsivity)

Stereotypies are purposeless, repetitive acts.

Bizarre postures and strange mannerisms

Altered facial expression, such as grimacing

Motionless, mute, expressionless

May adopt uncomfortable or contorted postures

Catalepsy is characterized by a waxy flexible state

Bouts of extreme hyperactivity, such as destructiveness

Impulsive behavior

Schizophrenia is NOT a violent disorder. While some individuals may engage in violent behavior, this is often due to untreated symptoms or co-occurring issues like substance abuse.

Disorder of conceptual thinking

Reflected in speech that is difficult to understand

Rapid shifts from one subject to another

New words (neologisms) invented

Patients withdraw from their families and friends and spend a lot of time alone.

Patients do not want to do anything

No longer interested in things that used to interest them

Disturbances in thinking leading to unintelligible speech

Derailment of speech (e.g., jumping from topic to topic)

Loosening of associations; failure to follow the train of thought

Poverty of speech (speech fails to convey sense/information), manifested as distorted or illogical speech

Cognitive deficits in selective attention, problem-solving, and memory

Blunted affect (decreased responsiveness to emotional issues)

Incongruous affect (expression of emotion inappropriate to circumstances)

Insight is an understanding of what is wrong.

Insight is typically lacking in schizophrenia, as patients often do not accept that anything is wrong or that treatment is necessary.

The Prodrome

Occurs in late teens/early twenties, often mistaken for depression or anxiety.

Can be triggered by stress.

The Active/Acute Phase

Onset of positive symptoms.

Differentiation of what is real and not real becomes difficult.

Remission

Treatment leads to a return to ‘normality.’

Relapse

Schizophreniform positive symptoms persist for at least a month but less than 6 months.

Genetics

Schizophrenia has a genetic component, with higher risk if a close family member has the disorder.

Multiple genes contribute to susceptibility.

Environmental Factors

Stressful life events, prenatal infections, or complications during birth can contribute to the development of schizophrenia.

Drug use, especially during adolescence, can also trigger or worsen the condition.

Monozygotic twins (identical twins)

If one twin is diagnosed with schizophrenia, there is a 50% chance the other twin will develop it as well.

Dizygotic twins (fraternal twins)

If one twin is diagnosed with schizophrenia, the risk for the other twin is around 14%.

Sickle-cell disease, cystic fibrosis, and colour blindness

These disorders have known genetic anomalies that lead to their development.

Candidate genes for schizophrenia

Examples include COMT, DISC1, and GRM3.

Genetic risk

Possessing these abnormal genes does not guarantee the development of schizophrenia. Likewise, some individuals with schizophrenia may not have these specific genetic abnormalities.

Season of birth

Exposure to influenza during pregnancy, such as during the 1957 epidemic, increases schizophrenia risk.

Birth complications

Low birth weight, premature birth, and asphyxia during birth are associated with early-life stress and an increased risk of schizophrenia.

Pregnancy-related recommendations

Pregnant women in the UK are advised to be vaccinated against seasonal flu to reduce the risk.

Moving country

Refugee immigrants are at higher risk than non-refugee immigrants (Swedish study).

Early-life bereavement

Loss of a first-degree relative during childhood increases risk.

Loss of job/home/relationship

Major life stressors in early life may trigger schizophrenia.

Abuse

Physical, emotional, or sexual abuse increases the risk of schizophrenia.

How does drug use relate to schizophrenia? (3)

Genetics

Schizophrenia isn’t directly inherited, but it can run in families.

Risk genes include gene deletions and mutations.

Environmental Factors

Pregnancy/birth complications, stress, and drug use can contribute to schizophrenia risk.

Nature

Genetic factors play a significant role in the risk of developing schizophrenia.

Nurture

Environmental factors like stress and drug use also contribute to the development of schizophrenia.

Dopamine Hypothesis

Abnormal dopamine activity in certain brain regions is implicated in schizophrenia.

Brain Structure Differences

Structural abnormalities in the brain, such as enlarged ventricles, are observed.

Hypofrontality

Reduced activity in the prefrontal cortex, linked to cognitive and negative symptoms.

NMDA Receptor Hypofunction

Dysfunction in NMDA receptors can contribute to psychotic symptoms.

Oxidative Stress and Neuroinflammation

Increased oxidative stress and neuroinflammation may play a role in the development of schizophrenia.

Movement

Dopamine is essential for motor control, with dysfunction linked to movement disorders like Parkinson's disease.

Cognition

Dopamine plays a role in cognitive processes, including attention, memory, and problem-solving.

Emotions

Dopamine is involved in regulating emotional responses, affecting mood and emotional stability.

Motivation

Dopamine influences motivation and goal-directed behavior, impacting drive and reward-seeking actions.

Reward

Dopamine is central to the brain's reward system, reinforcing behaviors by releasing dopamine in response to pleasurable stimuli.

Schizophrenia is associated with overactivity of dopamine (DA) in specific brain regions, particularly in the mesolimbic pathways, leading to positive symptoms such as hallucinations and delusions.

Hyperdopaminergic activity in the mesolimbic system is linked to positive symptoms (e.g., hallucinations, delusions).

Increased D2 receptor activity is a key feature of this overactivity.

D2 antagonists, like antipsychotic drugs, work by blocking these receptors, reducing the positive symptoms.

Hypodopaminergic activity (low dopamine levels) in the mesocortical system is associated with negative symptoms of schizophrenia, including cognitive deficits and emotional flatness.

This is linked to decreased D1 receptor activity, contributing to impaired cognition and motivation.

The D4 receptor may be involved in schizophrenia, but selective D4 antagonists have not been effective in treating the disorder, suggesting that its role might not be as significant as previously thought.

One theory suggests that schizophrenia could be caused by an endogenous dopamine derivative or a psychotogen (a substance that induces psychosis).

However, this theory remains controversial and the exact mechanism is not yet fully understood.

Amphetamine enhances dopamine (DA) release and produces schizophrenia-like symptoms (Carlsson 2000).

In schizophrenic patients, amphetamine enhances DA release more than in controls, which worsens the disease.

D2 agonists produce stereotyped behavior, which is characteristic of the overactivity of dopamine, particularly in the mesolimbic system.

D1 agonists do not cause this stereotyped behavior.

Reserpine depletes dopamine levels, which controls positive symptoms of schizophrenia by reducing dopamine activity in the brain.

There is a strong correlation between D2 receptor blocking activity and the antipsychotic action of drugs used to treat schizophrenia.

Dopamine release occurs specifically in the mesolimbic and mesocortical regions of the brain in schizophrenic patients, but not in the nigrostriatal pathway, which is involved in movement regulation

No clear change in CSF HVA (Homovanillic Acid) concentration (a marker of dopamine activity).

No change in dopamine (DA) receptors in drug-free patients.

The increase in D2 receptors in samples is often attributed to drug treatment rather than intrinsic changes in the brain.

Dopamine hypothesis

Brain structure differences

Hypofrontality (decreased activity in the prefrontal cortex)

NMDA receptor hypofunction (impaired glutamate signaling)

Serotonin involvement

Oxidative stress and neuroinflammation (damage to brain cells caused by inflammation and oxidative damage).

Slightly smaller brain size

Reductions in grey matter

Enlarged lateral ventricles and smaller hippocampus

The twin with schizophrenia (SCZ) shows larger lateral ventricles and reduced grey matter.

The healthy twin does not show these significant structural differences.

Dopamine hypothesis

Brain structure differences

Hypofrontality

NMDA receptor hypofunction

Oxidative stress

Neuroinflammation

Reduced blood flow to the frontal cortex

Reduced activity in the frontal cortex

Role of the frontal cortex: Involved in higher cognitive functions, including decision making, planning, social behavior, and working memory.

Symptoms related to reduced frontal activity:

Cognitive deficits (e.g., impaired memory and attention)

Negative symptoms (e.g., lack of motivation, social withdrawal)

Difficulty with executive functioning (e.g., poor decision making, inability to plan or organize)

Neurotransmitter involved: Glutamate

Action: Acts on NMDA receptors in the prefrontal cortex and other brain regions.

Psychotic symptoms: Induce hallucinations and thought disorders similar to those seen in schizophrenia

Mechanism: Block NMDA receptors, leading to a reduction in glutamate activity

Symptoms observed: Stereotyped behaviors, social withdrawal, and cognitive disturbances.

Decreased glutamate levels and reduced glutamate receptor density in the prefrontal cortex

Transgenic mice with reduced NMDA receptor expression show symptoms similar to schizophrenia, including:

Stereotyped behavior

Decreased social interaction

Responsiveness to antipsychotics

LSD: A partial 5-HT agonist known to induce hallucinations, demonstrating serotonin’s role in psychosis.

Antipsychotics: Many target and antagonize 5-HT receptors, suggesting serotonin's involvement in the pathophysiology of schizophrenia.

Current theory: Overstimulation of mesolimbic D2 receptors, hypoactivity of frontal cortical D1 receptors, and reduced prefrontal glutaminergic activity are key mechanisms in schizophrenia, with 5-HT playing a role in this dysfunction.

Antipsychotics: D2 receptor antagonists and 5-HT receptor antagonists help treat symptoms.

Example drugs: Atypical antipsychotics (e.g., clozapine, risperidone) target both dopamine and serotonin receptors to balance the activity of these neurotransmitters.

Pharmacological: Includes antipsychotics that target dopamine and serotonin receptors.

Psychotherapeutic: Cognitive Behavioral Therapy (CBT) aims to help patients manage symptoms and reduce the distress caused by hallucinations or delusions.

Current therapies: Antipsychotic medications (e.g., atypical and typical antipsychotics) to manage positive symptoms (hallucinations, delusions).

Future therapies: Research is ongoing for targeted treatments involving glutamate, serotonin, and novel drug classes that may offer better symptom management with fewer side effects.

ECT is used in severe cases of schizophrenia, particularly when medications are ineffective or symptoms are life-threatening, and it involves applying electrical currents to induce controlled seizures, which may help reset brain activity.

Typical antipsychotics: Also known as first-generation antipsychotics, developed in the 1950s.

Mechanism: Primarily antagonize D2 receptors, which helps reduce positive symptoms of schizophrenia.

Atypical antipsychotics: Also known as second-generation antipsychotics, developed in the 1980s.

Mechanism: Primarily antagonize both D2 and 5-HT2A receptors, targeting both dopamine and serotonin systems to manage positive and negative symptoms.

D2 receptor antagonism: Blocking D2 receptors can lead to sedation due to its effects on dopamine-related pathways.

Central H1 receptor antagonism: Antagonizing histamine H1 receptors in the central nervous system also contributes to sedative effects.

Increased prolactin secretion: Antipsychotics can cause an increase in prolactin levels.

Gynaecomastia: Increased prolactin can lead to the development of breast tissue in males.

Milk secretion: Prolactin increases can cause galactorrhea, or spontaneous milk secretion.

Menstrual irregularities and impotence: Women may experience menstrual cycle disruptions, and men may have impotence due to the hormonal imbalance.

α1-adrenoceptor antagonism: Antipsychotics can block α1-adrenoceptors, which are involved in vasoconstriction.

Leads to hypotension: Blocking these receptors can cause dilation of blood vessels, resulting in lower blood pressure (hypotension).

Dry mouth: Muscarinic acetylcholine receptor (mAChR) antagonism decreases salivary secretions.

Blurred vision: Pupillary muscles are affected by the blockade, causing blurred vision.

Constipation and Urinary retention: Smooth muscle contraction is reduced, leading to constipation and urinary retention.

Alleviation of EPSE symptoms: Blockade of mAChRs at the neuromuscular junction helps alleviate extrapyramidal symptoms (EPSEs) like tremors and rigidity.

Cognitive impact: Anticholinergics may have a detrimental impact on cognition, reducing mental clarity.

Anhedonia is the inability to feel pleasure in normally pleasurable activities

Aetiology refers to the cause or set of causes that lead to a disease or condition.

A candidate gene is any gene thought to be likely to cause a disease.

A risk gene is essentially a candidate gene that increases the likelihood of developing a particular condition or disease.

CBT is a type of psychotherapy in which negative thought patterns about oneself and the world are challenged in order to alter unwanted behavior patterns or treat mood disorders like depression.

ECT is a treatment that involves sending an electric current through the brain to trigger an epileptic seizure to relieve symptoms of some mental health conditions.

The mesocortical pathway is a dopaminergic pathway that connects the ventral tegmentum to the prefrontal cortex.

The mesolimbic pathway is a dopaminergic pathway that connects the ventral tegmental area in the midbrain to the ventral striatum of the basal ganglia in the forebrain.

The nigrostriatal pathway is a dopaminergic pathway that connects the substantia nigra pars compacta (SNc) with the dorsal striatum (caudate nucleus and putamen).

The tuberoinfundibular pathway consists of dopamine neurons that project from the arcuate nucleus (infundibular nucleus) in the tuberal region of the hypothalamus to the median eminence.

Prolactin is a hormone released from the anterior pituitary gland that stimulates milk production after childbirth.

Antipsychotics are a class of drugs designed to treat severe psychiatric conditions such as schizophrenia.

EPSEs are serious side-effects of antipsychotic and other drugs that affect movement

Agranulocytosis is a deficiency of granulocytes in the blood, which causes an increased vulnerability to infection.