Schizophrenia

Schizophrenia, a chronicpsychiatric condition in which the in which there are disturbances in the perception, thought, emotion and behaviour for a period of >6 months. It falls under a group of disorders known as psychotic disorders due to the hallmark symptoms of delusions, hallucinations, disorganised speech and impairments of cognition.

🏘️ Epidemiology

In the UK and globally, about 1% of the population is affected. Both men and women are affected equally, however, males tend to present at an earlier age compared to women (<25 years old for males and <35 years old for females).

It tends to have higher prevalence in urban areas.

First-degree relatives tend to have a 10% risk.

Pathophysiology

The Diathesis-Stress Model suggests that schizophrenia occurs a result of interactions from pre-existing vulnerabilities (diathesis) and external stressors. These stressors can be biological and environmental both. Such environmental stressors may include trauma while biological stressors include substance misuse, infections, obstetric complications and genetics (some genes implicated include DISC1, NRG1, COMT, DTNBP1).

How schizophrenia is precipitated is not well understood, but there are both neurochemical theories and neuroanatomical theories that are hypothesised:

Neurochemical theories

Dopamine hypothesis - this hypothesis suggests that an overactivity and underactivity of dopamine in certain regions lead to the positive and negative symptoms in the disease.

The 4 main dopaminergic pathways include:

Mesolimbic pathway - an increase of dopamine in the mesolimbic pathway leads to the positive symptoms.
Mesocortical pathway - a decrease in dopamine in the mesocortical pathway leads to the negative symptoms.
Nigrostriatal pathway - a decrease in dopamine in the nigrostriatal pathway lead to the motor symptoms.
Tuberoinfundibular pathway - this pathway regulates the release of prolactin and is affected by antipsychotic medications.

Glutamate hypothesis - this hypothesis suggests that dysfunction of the glutamatergic system aids disease development. Particularly with regards to the NMDA receptors. Antagonists of the NDMA receptors may mimic both positive and negative symptoms.
Serotonin hypothesis - this hypothesis suggests that an overactivity of serotonin in certain regions contribute particularly to the negative schizophrenia symptoms. This may be supported with the fact that medications that block the serotonin receptors are more effective for the negative symptoms.

Neuroanatomical abnormalities

Enlarged lateral and third ventricles - this suggests cortical atrophy and a loss of brain volume.
Reduced gray matter - in the prefrontal cortex, temporal lobes, hippocampus and amygdala.
Hypofrontality - reduced activity in the frontal lobes.

⚠️ Risk factors

Family history
Genetic mutations - DISC1, NRG1, COMT, DTNBP1.
Maternal infections - such as influenza, rubella, toxoplasmosis and CMV.
Obstetric complications
Urban upbringing
Childhood trauma
Low socioeconomic status
Substance use
Stressful life events

😷 Presentation

Often times schizophrenia manifests with a prodrome of negative symptoms followed by positive symptoms and then a residual phase, during which patients go back to their normal baseline before gradually moving to another prodrome state

So what are the positive and negative symptoms?

Negative symptoms of schizophrenia:

Flat affect - reduced or absent emotional expression.
Avolition - reduced or absent ability to initiate purposeful activities.
Alogia - impaired thinking that manifests with reduced speech output or poverty of speech (e.g., always replying to questions with one-word answers).
Anhedonia - inability to feel pleasure from activities that were formerly pleasurable or from any new positive stimuli.
Apathy - lack of emotion or concern, especially with regard to matters that are normally considered important.
Asociality - emotional or social withdrawal.

Positive symptoms of schizophrenia:

Psychosis

Hallucinations - usually auditory.
Delusions - grandiosity, ideas of reference, persecutory, paranoia.
Disorganised thought or speech - loose associations, word salad, etc.

Abnormal motor behaviour

Grossly disorganised behaviour - an abnormal behaviour characterised by inadequate goal-directed activity (i.e. purposeless movements) and bizarre emotional responses (i.e. smiling or laughing when inappropriate).
Catatonia - may not be able to move, or may seem ”stuck” in an odd, awkward posture.

⭐️ The ICD-11 diagnostic criteria for schizophrenia require at least 2 features to be present, with at least 1 being a positive symptom, for most of the time for 1 month or more.

In addition to the negative and positive symptoms, there may be some cognitive symptoms and mood symptoms too:

Cognitive symptoms

Inattention
Impaired memory
Poor executive function

Mood symptoms and associated mental health conditions:

Depression
Social phobias and specific phobias
Post-traumatic stress disorder
Obsessive-compulsive disorder
Panic disorder

🗂️ Subtypes

We will discuss the different types of schizophrenia and their associated features.

Paranoid schizophrenia

This is the most common type of schizophrenia.

Stable, paranoid delusions
Persecutory delusions - believing someone is out to get them.
Auditory hallucinations
Preserved cognition
No negative symptoms
Organised thoughts and speech

Disorganised (hebenephrenic) schizophrenia

This typically occurs between the ages of 15-25 years old.

Disorganised speech

Word salad - words are jumbled together without any logical structure, making it incomprehensible.
Loose associations - ideas shift from one topic to another with little or no logical connection. The person’s train of thought does not stay on track and may seem random.
Circumstantial speech - goes off on tangents with excessive, unnecessary details, but eventually returns to the main point.

Negative symptoms
Social isolation
Delusions

Catatonic schizophrenia

This individual may be affected by catatonia (abnormality of movement and behaviour arising from a disturbed mental state) and is unable to move or seems stuck in a strange, awkward posture.

Stupor
Akinetic or retarded catatonia - severe motor slowness or absence of movement.
Excited catatonia - hyperactive, agitated form of catatonia where the person shows excessive but purposeless movement.
Malignant catatonia - severe, life-threatening form of catatonia with autonomic instability and high fever, resembling neuroleptic malignant syndrome (NMS).
Posturing - holding an awkward position for long periods.

Residual schizophrenia

This is characterised by predominantly negative symptoms and applies to those who have had at least 1 episode of schizophrenia but are not experiencing prominent positive symptoms or disorganised behaviour. It often occurs after the psychotic phase of the disorder.

Simple schizophrenia

This is a rare subtype of schizophrenia characterized by a gradual decline in functioning without prominent positive symptoms (hallucinations or delusions). Instead, it primarily presents with negative symptoms like social withdrawal, apathy, and reduced motivation.

It is rarely diagnosed in the UK.

Some other psychotic disorders that are similar to schizophrenia include:

Schizoaffective disorder - combines mood disorder features with psychotic symptoms. By definition, the psychotic symptoms must be more dominant than the mood symptoms and psychosis must have been present for at least 2 weeks in the absence of any mood disturbance.
Brief psychotic disorder - consists of delusions, hallucinations, or other psychotic symptoms for at least 1 day but <1 month, with eventual return to normal premorbid functioning.
Schizophreniform disorder - characterised by symptoms identical to those of schizophrenia but that last ≥1 month but <6 months.
Delusional disorder - characterised by the presence of 1 or more non-bizarre delusions that persist for at least 1 month without any other prominent psychotic symptoms, such as hallucinations, disorganised speech, or grossly disorganised or catatonic behaviour.

🔢 Classification

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) classifies schizophrenia based on the number and pattern of episodes as well as the residual effects:

Multiple episodes (currently in partial remission) - when the patient is between acute episodes and there are residual symptoms that do not meet the full diagnostic criteria.
Multiple episodes (currently in full remission) - when no clinically significant symptoms exist between episodes.
Continuous - when symptoms exist throughout most of the disease course.
First episode (in partial or full remission) - if after the initial episode, minimal or no symptoms exist.
Unspecified - used when an unspecified pattern has been present.

The DSM also provides a symptom-based severity specifier which enables clinicians to rate the intensity on a standardised scale. The severity may be rated using a quantitative assessment of the primary symptoms of psychosis (abnormal psychomotor behaviour, delusions, disorganised speech, hallucinations, and negative symptoms). The peak severity of the symptoms over the last week is rated on a 5-point scale ranging from 0 (not present) to 4 (present and severe).

The International Classification of Diseases (ICD-11) classifies the schizophrenia into different subtypes based on the pattern and frequency of episodes as well:

Schizophrenia, first episode - experiencing symptoms that meet the diagnostic requirements for schizophrenia (including duration) but never before experienced an episode during which diagnostic requirements for schizophrenia were met
Schizophrenia, multiple episodes - experiencing symptoms that meet the diagnostic requirements for schizophrenia (including duration) and also previously experienced episodes during which diagnostic requirements were met, with substantial remission of symptoms between episodes.
Schizophrenia, continuous - symptoms fulfilling all definitional requirements of schizophrenia have been present for almost all of the illness course over a period of at least 1 year, with periods of subthreshold symptoms being very brief relative to the overall course
Other, specified episode of schizophrenia
Schizophrenia, episode unspecified

🔍 Investigations

According to the ICD-11, a diagnosis of schizophrenia requires the presence of at least two of the following symptoms for a duration of one month or longer, with at least one symptom from the first four categories (positive symptoms):

Persistent hallucinations in any sensory modality, particularly when accompanied by fleeting or partial delusions without distinct emotional content, persistent over-valued ideas, or occurring on a daily basis for weeks or months.
Disorganised thinking, which may include thought echo, thought insertion or withdrawal, and thought broadcasting.
Delusions of control, influence, or passivity, specifically linked to bodily sensations, limb movements, or particular thoughts and actions.
Persistent delusions that are culturally incongruent and entirely implausible, such as claims of possessing supernatural abilities, extreme political or religious identities, or communication with extraterrestrial beings.
Disruptions in thought processes, leading to incoherent or irrelevant speech, or the use of newly invented words (neologisms).
Catatonic behaviors, which may include excessive movement, unusual postures, waxy flexibility, negativism, mutism, or states of stupor.
Negative symptoms, such as pronounced apathy, reduced speech output, and diminished or inappropriate emotional responses. These symptoms must be clearly distinguishable from those caused by depression or medication side effects.
Severely disorganised behavior, which affects the ability to carry out goal-directed activities. This may manifest as bizarre, purposeless actions or emotional responses that are unpredictable and interfere with structured behavior.

🧰 Management

🧰

Management of schizophrenia:

Schizophrenia is predominantly managed in secondary care but we will also discuss the primary care approach to managing the disease.

It is important in any patient with psychotic symptoms that we undertake a risk assessment of harm to themselves or others. This involves looking at their history of self-harm or ideation of it, substance abuse and the level of support they have. If they are deemed to be at high-risk then a same-day psychiatric mental health assessment needs to be done. If they need admission to hospital, they should be persuaded to go voluntarily but if they decline they may be admitted under sections 2 or 4 of the Mental Health Act.

Management in primary care

Continuing medication started in secondary care - as well as any monitoring necessary for this.
Monitoring the symptoms - a crisis plan should be advised by secondary care in case relapse does occur.
Re-referral to secondary care - if there is a poor response or adherence to treatment, if function significantly declines, if there is comorbid substance use.

Ultimately the management in primary care is directed by the secondary care team.

Management in secondary care

If the patient is at risk of developing a psychotic disorder then early intervention is necessary. This includes interventions such as:

Individual CBT
Treatment for co-existing anxiety depression personality disorders or substance misuse.

If/once the individual is diagnosed with the psychotic disorder then secondary care needs to initiate the treatment using the following:

🥇 A trial of a first-generation or second-generation antipsychotic in conjunction with:

Family intervention
Individual CBT - of at least 16 sessions.
Arts therapies - particularly if there are negative symptoms.

If the antipsychotic does not work then they should be trialled on an alternative antipsychotic.

💡 We will discuss antipsychotics in depth below.

🥈 Clozapine - clozapine may specifically be used when schizophrenia is treatment resistant (not response to the trial of 2 antipsychotics). It requires management exclusively in secondary care due to its risk of neutropenia and agranulocytosis. As such an individual needs to be monitored weekly for 18 weeks and then every 2 weeks for the subsequent 18 weeks. After the first 36 weeks of intensive monitoring they can be managed every 4 weeks afterwards.
Care plan - a care plan needs to be put in place for the patient with a copy sent to primary care. This will define the roles of the primary and secondary care team, which include:

Crisis plan
Advance statement - a written statement that is signed by the individual when they are well. It sets out how they would prefer to be treated/not treated if they were to fall ill in the future and are unable to give consent on a decision.
Clinical contacts - in case of emergency or an impending crisis.

Reviewing the psychotic/schizophrenic patient

Annual reviews (at least) need to be conducted in GP. The review should assess the symptom control and should screen for psychotic symptoms. It should enquire about personal function to see if they are deteriorating, and also assess for any concomitant depression or anxiety symptoms. It Is is important to assess medication adherence and side effects

How do we screen for psychotic symptoms?

We can ask the following questions to screen for psychotic symptoms:

Do you hear voices when nobody is around?
Do you ever think that people are talking or gossiping about you, maybe even thinking they are out to get you?
Do you ever think that somehow people can pick up on what you are thinking or can manipulate what you are thinking?

Certain tests need to be done:

Fasting glucose or HbA1c
Lipid profile
U&Es
FBC
LFTs
Prolactin - but not if they are on aripiprazole, clozapine, quetiapine, olanzapine.
ECG - if they are taking haloperidol, pimozide, sertindole, if they have had a previous ECG abnormality, or if they have an additional risk factor for QT prolongation (such as taking another medication that can increase the QT interval such as erythromycin, co-trimoxazole, or pregabalin).

💊

Antipsychotics

Antipsychotics are classified as 1st generation (typical antipsychotics) or 2nd generation (atypical antipsychotics) antipsychotics.

1st generation antipsychotics are thought to work by blocking the D2 receptors in the brain. 2nd generation antipsychotics act on a wider range of receptors (including D2, 5HT2, muscarinic, histamine, alpha adrenoreceptors, and others). The effect on these receptors is what leads to extrapyramidal symptoms (EPS).

Generally, 2nd generation antipsychotics have fewer EPS compared to first generation antipsychotics. However, they have other important adverse effects, such as arrhythmias, weight gain, sexual dysfunction, glucose intolerance, hyperprolactinaemia (which is why prolactin levels are checked routinely).


Benperidol	Amisulpride
Chlorpromazine	Aripiprazole
Flupentixol	Clozapine
Haloperidol	Olanzapine
Levomepromazine	Paliperidone
Pericyazine	Quetiapine
Perphenazine	Risperidone
Pimozide	Zotenpine
Prochlorperazine
Promazine
Sulpride
Trifluoperazine
Zuclopenthixol

Antipsychotics can be given orally or as depot injections. Antipsychotic depot injections are used for maintenance therapy when adherence to oral treatment is unreliable. They are administered every 1–4 weeks.

There is no 1st line antipsychotic drug that suits all psychotic people. So, the choice is multifactorial depending on the person's personal choice, medication history, degree of sedation required, risk of particular adverse effects, and the degree of negative symptoms (usually these are improved better with 2nd gen antipsychotics).

The only exception is clozapine, which is significantly more effective than all other antipsychotics, and hence is offered to people who do not respond adequately to 2 other antipsychotics.

⭐️ The most common side effect of clozapine is constipation (due to inhibiting peristalsis)
Drowsiness
Agranulocytosis (1%) and neutropenia (3%) - as such FBC monitoring is necessary every month.
Reduced seizure threshold - can induce seizures in up to 3% of patients
Myocarditis - a baseline ECG should be taken before starting treatment
Hypersalivation
Hypertension or postural hypotension
Weight gain
Smoking cessation can increase clozapine blood levels

💡 It is recommended to measure a clozapine level in the presence of an infection in anticipation of toxicity.

💡 Blood lipids, bloods glucose, and weight should be regularly checked (baseline, after a few months, and then yearly) - for all antipsychotics

Adverse effects:

EPS - more common with 1st gen antipsychotics:

Dystonic reactions - abnormal spasms of the face and body [usually within the 1st 1-5 days] like torticollis or oculogyric crisis. Can be alleviated with anticholinergic drugs like procyclidine or biperiden
Pseudoparkinsonism (tremor, bradykinesia, and rigidity) (usually 1-4 weeks after initiating Rx). Can be alleviated with anticholinergic drugs like procyclidine
Akathisia - a feeling of inner restlessness and inability to sit still [usually 1-2 months after initiating Rx]. Can be relieved by lowered the medication dose, B blockers, benztropine, BZD's
Tardive dyskinesia - a late-onset movement disorder that can occur with prolonged use of antipsychotics (usually months-years after initiating the medication).

TD is thought to be caused by long-term blockade of dopamine receptors in the nigrostriatal dopamine pathway, causing receptor upregulation (ie, increase in number) and compensatory supersensitivity of postsynaptic neurons.

It is characterised by rhythmical, involuntary movements, usually lip-smacking and tongue rotating (orofacial dyskinesia), although it can affect the limbs and trunk.

It may be persistent and can sometimes worsen on treatment withdrawal.

Neuroleptic malignant syndrome - a rare but potentially fatal adverse effect of all antipsychotics. It tends to happen a few days after starting the medication. Tetrad: hyperthermia, muscle rigidity, autonomic instability (hypotension, tachycardia, sweating, etc), altered mental status (confusion, fluctuating consciousness). Bloods: raised LFT's, WCC, CK. Management involves stopping the causative medications and supportive care (e.g., IV fluids and sedation with benzodiazepines). Severe cases may require treatment with bromocriptine (a dopamine agonist) or dantrolene (a muscle relaxant).
Weight gain - common in all antipsychotics but more so in 2nd gen. In general, clozapine and olanzapine have the greatest potential to cause weight gain, followed by chlorpromazine, quetiapine, and risperidone.
Hyperprolactinaemia - with most antipsychotics, and may lead to galactorrhoea, amenorrhoea, gynaecomastia, hypogonadism, sexual dysfunction, and an increased risk of osteoporosis.

This is due to antipsychotics disrupting the tuberoinfundibular pathway, which connects the hypothalamus to the pituitary gland and is responsible for the tonic inhibition of prolactin secretion.

Dyslipidaemia
Sedation - performance of skilled tasks (such as driving) may be affected and the effects of alcohol are enhanced.
Anticholinergic effects (dry eyes, dry mouth, dry skin, urinary retention, constipation, skin flushing)
Impaired glucose tolerance - more common in people with schizophrenia
QT interval prolongation - the most widely reported cardiac conduction defect
VTE
Neutropenia - stop the suspected drug if neutrophils fall below 1.5 x 109/L
Abnormal LFTs - stop the suspected drug if LFTs suggest hepatitis (transaminases rise to 3 times normal) or PT or albumin are abnormal
Photosensitivity
DRESS
Pneumonia - unclear mechanism
Diplopia - uncommon
Restless leg syndrome - uncommon

Specific to a certain antipsychotic:

Sleep apnoea syndrome - with quetiapine
Cardiomyopathy, myocarditis and cutaneous vasculitis - with quetiapine, but a causal relationship has not been established
Increased stroke risk in dementia patients - olanzapine and risperidone are associated with an increased risk of stroke in elderly people with dementia