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29th January 2024

Schizophrenia

Background

Epidemiology

Schizophrenia has an estimated prevalence of 14.5 per 1000 across all ages and populations in the UK. It usually develops in early to late adulthood and rarely before the age of 10. The average age of onset in men is between 18-25 and ages 25-35 for women, sometimes occurring with a second peak around menopause. Individuals with Schizophrenia are more likely to have other mental comorbidities such as depression, alcohol and substance misuse, personality disorder, and anxiety disorders like post-traumatic stress disorder (PTSD) or obsessive-compulsive disorder (OCD).

Pathophysiology

The exact pathophysiology of Schizophrenia remains unknown; however, there is significant evidence to suggest a complex interaction between genes and the environment.

Genetic Factors

Genes are believed to play a pivotal role in the development of schizophrenia. This has been evaluated through twin studies conducted on monozygotic and dizygotic twins. Studies have demonstrated that the risk of developing schizophrenia is between 10-15% in dizygotic twins and 40-50% in monozygotic twins. This is compared to the lifetime risk of 1% in the general population. Although we understand that there is a strong genetic predisposition, the exact causative genes have yet to be identified.

Biochemical factors

Ongoing research has identified a variety of chemicals and neurotransmitters that play a role in the development of schizophrenia. Dopamine is one of the main neurotransmitters that has been found in excess within mesolimbic areas of the brain, causing positive symptoms such as hallucinations. Other substances, such as opioids and amphetamines increase dopaminergic activity, thus contributing to the causation of psychosis. In addition to Dopamine, an excess of Serotonin is also recognised to likely be causative of psychosis. This pathway is targeted by Second-Generation Antipsychotics working antagonistically at Serotonin receptors(5-HT2-R).

Environmental Factors

The fact that monozygotic twins only have a 50% chance of developing schizophrenia, supports the idea that there is a complex interaction between genes and environment that influences their risk. There are a number of recognised environmental factors that are thought to predispose an individual to developing schizophrenia. This includes:

  • Obstetric complications (haemorrhage, preterm labour, foetal hypoxia)
  • Cannabis, amphetamine and cocaine (increase dopaminergic activity)
  • Smoking
  • Immigration: There is notably a higher prevalence of schizophrenia in immigrant populations. This is thought to be due to higher levels of stress activating latent genetic factors
  • Neurodevelopmental abnormalities in utero
  • High expression households: levels of emotion expressed in a household may be ‘high’ or ‘low.’ The emotions can be positive (reassuring, warm) or negative (hostile, critical). High levels of both positive and negative emotions can have a significant impact on the development, management and relapse of schizophrenia. For example, high levels of negative emotions are a known psychological stressor which could trigger a relapse, whereas an over-involved family impedes the development of independent coping strategies.

References

Presentation

Schizophrenia typically presents as a syndrome across 4 main symptom domains: Positive symptoms, negative symptoms, cognitive impairment and mood and anxiety symptoms. Each individual will have a unique combination that varies in onset, duration and severity.

Positive symptoms 

Positive symptoms are those that distort the perception of reality. These include:

  • Hallucinations: These can affect any of the five senses (auditory, visual, olfactory, gustatory or tactile). Auditory hallucinations are the most common form in schizophrenia and seem to respond the most to antipsychotics. Often, they present as voices, but they can also be sounds. Olfactory, tactile and visual hallucinations are less common and are more likely to be associated with organic pathology, which requires further investigations.
  • Delusions: This is defined as a fixed, false belief that is unexplained by cultural norms and that which is unshakeable in the face of strong contradiction. Delusions can be bizarre or non-bizarre. A bizarre delusion could be that an individual believes that they are a shaman that transports spirits across different realms, whereas a non-bizarre delusion may be that an individual believes that HMRC is spying on them for not paying their taxes. Delusions can be further categorised as:
    • Ideas of reference: Individual believes that there is a personal significance behind coincidental or innocuous events, e.g. certain words or songs on TV are relaying a message to the individual
    • Grandiose: Individual believes that they have some sort of special significance, skill or power; e.g. they believe that they are related to the Queen of England
    • Paranoid: Individual believes that they are vulnerable and being targeted. This often leads to forensic issues such as carrying weapons and unpredictable, violent behaviour. Alternatively, it may lead to self-isolation or ‘going off the grid.’ Paranoia can lead to significant issues with treatment compliance and poor contact with services due to fear of being manipulated or poisoned
    • Nihilistic: Individual believes that they are dead, rotting or have lost their internal organs
    • Delusion of thought interference: Thought insertion, withdrawal, and broadcast
    • Delusions of passivity: Belief that an external source is controlling their body and mind
  • Thought disorder: Individuals demonstrate disorganised thinking, which can be observed through abnormal behaviour, speech, and written language.
    • Thought blocking: disruption in the train of thought such that the individual suddenly stops midway through talking
    • Flight of ideas: rapid speech that digresses from one topic to another before completion
    • Tangential speech: digressing off-topic and never returning to the initial conversation
    • Circumstantial speech: Individual offers a lot of irrelevant details and wanders off topic, but eventually, they are able to answer the question in a ’roundabout’ way
    • Neologisms: Creation of new words
    • Word salad: a jumble of random, incoherent words

Negative symptoms

Negative symptoms are those that withdraw the individual from normal social functioning. These include:

  • Anhedonia: loss of interest in previously enjoyable activities and relationships
  • Unable to maintain personal hygiene or activities of daily living
  • Social withdrawal: not going out or speaking to anyone
  • Lack of energy, motivation and excessive sleeping
  • Flat affect: restricted range of emotional expressions
  • Thought poverty: slowness in thinking, reactivity and speech

Cognitive impairment

Studies have shown that individuals with schizophrenia demonstrate impaired cognitive performance across several cognitive domains. This includes a reduction in:

  • Speed of processing information
  • Attention and vigilance
  • Working memory
  • Reasoning and problem-solving
  • Verbal comprehension
  • Social cognition and awareness

Mood and Anxiety Symptoms 

Mood and anxiety symptoms occur at high rates in schizophrenic patients compared to the general population.

Depression

Depression can present in Schizophrenic patients during the acute psychotic phase or after as a distinct depressive episode. It is associated with poorer outcomes such as prolonged hospital admission, re-hospitalisation, severe cognitive impairment, significant decline in social functioning, poorer response to pharmacological treatments and increased attempted and completed suicides.

Depression can sometimes be mistaken as negative symptoms of schizophrenia; however, the distinction can be made when you consider the fact that depression will likely present with cognitive symptoms of depression such as guilt, shame, worthlessness and tearfulness. In some individuals, a ‘depressive prodrome’ precedes a Schizophrenic relapse; this can be anticipated in patients who have had similar episodes

Anxiety

Individuals with schizophrenia can either experience anxiety as part of their schizophrenia syndrome (this is called secondary anxiety) or as an additional disorder. An example of this is when an individual develops anxiety due to terrifying hallucinations or paranoid delusions.

First Rank Symptoms

These are a group of symptoms identified by German psychiatrist Kurt Schneider as being characteristic of schizophrenia, henceforth known as ‘Schneider’s first rank symptoms’. In practice, first-rank symptoms can often overlap with other disorders and, therefore, are not strictly pathognomonic of schizophrenia. Nonetheless, they are useful as a screening tool to prompt further evaluation of each symptom domain in schizophrenia. These are:

  1. Auditory hallucinations: third person running commentary or thought echo (hearing thoughts spoken aloud)
  2. Somatic hallucinations: bodily sensations experiences such as crawling insects
  3. Delusion of thought interference: Thought insertion, withdrawal, and broadcast
  4. Delusions of control or passivity phenomenon: the belief that an external source is controlling the individual

References

Assessment

It is important to establish the cause of psychosis, its onset, duration, and its effect on the individual’s personal functioning. This is best done via a comprehensive psychiatric assessment. Each domain should be assessed independently (positive symptoms, negative symptoms, cognition, mood and anxiety symptoms), noting severity, duration and impact on social functioning. Due to the nature of Schizophrenia, it may be difficult to obtain a coherent history from the individual themselves; therefore, it is important to take a collateral history from family, a friend or care worker. It is advisable to ensure that you are wearing an alarm pendant, chaperoned, and in clear line of an exit, as patient agitation can escalate rapidly. Within the assessment, it is particularly important to pay attention to areas such as history of substance misuse, family history of any mood or psychotic disorders and psychosocial history to identify any risk factors. A thorough risk assessment that includes an assessment of suicide risk, as rates of suicide in schizophrenic patients can be as high as 10%.

Investigations

Prior to initiating treatment with antipsychotics, a thorough physical health assessment must be conducted. This includes:

  • Baseline bloods (FBC, U+E, LFT, CRP), including lipids and HBA1C (due to increased risk of metabolic syndrome with antipsychotic use), Thyroid Function Test (risk of hypothyroidism), Prolactin (risk of hyperprolactinaemia), and Vit B12, Folate and Ferritin (patients may present in malnourished states)
  • ECG: Certain antipsychotics (e.g. Haloperidol) have a higher propensity for prolonging QTc interval or may induce ECG changes, thus obtaining a baseline to compare is essential
  • Pregnancy test: certain antipsychotics are teratogenic
  • Height, Weight, BMI: Patients taking antipsychotics have increased risk of metabolic syndrome
  • General physical examination
  • Vital Signs: This is of particular importance when patients are newly commenced on antipsychotics that have a high risk of neuroleptic malignant syndrome (e.g. Haloperidol, Chlorpromazine)
  • Urinalysis, including drug screening: can help in ruling out other causes of disordered behaviour, e.g. UTI, cocaine

Diagnosis

Schizophrenia should be suspected in any individual presenting with symptoms suggestive of psychosis and disorganised behaviour with significant deterioration in their social functioning. There are two diagnostic manuals that can aid in the diagnostic process: DSM-V and WHO ICD10. DSM-V is a classification manual used in the United States, whereas WHO ICD10 is used in the UK. For practical reasons, we will be discussing ICD10 diagnostic criteria.

Diagnostic criteria 

ICD10 outlines that at least one of the symptoms or syndromes listed under (1), or at least two of the symptoms and signs under (2) should be present most of the time during an episode, for 1 month (or at least some of the time most of the days). These symptoms MUST be in the absence of substance misuse or an organic cause (e.g. brain tumour, temporal lobe epilepsy) or significant mood disorder. Once a diagnosis of schizophrenia has been established, it can be further sub-classified based on prominent symptomatology.
1. At least ONE of the following must be present: 2. Or at least TWO of the following:
  1. Thought echo, thought insertion or withdrawal, or thought broadcast
  2. Delusions of control, influence, passivity, including specific thoughts, actions or sensations, delusional perception
  3. Hallucinatory voices giving a running commentary on the patient’s behaviour, discussing the patient amongst themselves, or other types of hallucinatory voices coming from some part of the body
  4. Persistent delusions of other kinds that are implausible and culturally irrelevant (e.g., being in control of spirits)
  1. Persistent hallucinations occurring every day for at least 1 month when accompanied by delusions (fleeting or half-formed) without clear affective content or when accompanied by persistent overvalued ideas
  2. Neologisms, breaks or interpolations in train of thought, resulting in incoherent, irrelevant speech
  3. Catatonic behaviour such as posturing, waxy flexibility, mutism and stupor
  4. Negative symptoms such as marked apathy, paucity of speech, blunting or incongruity of affect and responses

Source: Adapted from: World Health Organisation. ICD-10 classification of mental and behavioural disorders: Diagnostic criteria for research [internet]. World Health Organisation; 1993 [cited 2022 July 14]. Available from: https://apps.who.int/iris/bitstream/handle/10665/37108/9241544554.pdf 

Paranoid Schizophrenia:

This is the commonest type of Schizophrenia worldwide. To make the diagnosis, there must be a strong persecutory and paranoid nature to the delusions or hallucinations, often both. Disturbances in speech, affect, or catatonia may be present; however, they are characteristically not prominent. The most common paranoid delusions present are delusions of persecution or grandeur. Common examples of paranoid hallucinations include threatening and commanding auditory hallucinations. Paranoid schizophrenia is episodic with partial or complete remission of symptoms. In chronic cases, the symptoms may persist for several years without ever gaining insight. In such cases,  it can be difficult for the patient to adhere to a treatment plan. It may be appropriate to consult appropriate legal frameworks that will allow the covert administering of medication in the patient’s best interests.

Hebephrenic/disorganised Schizophrenia

This form of schizophrenia, also known as ‘disorganised schizophrenia,’ describes a presentation in which affective changes and disorganised behaviour and speech are prominent. Observing these individuals will identify extreme activity that is purposeless and non-constructive. Characteristically, their thought patterns and speech are obviously disorganised and incoherent. They may be seen laughing or smiling inappropriately, demonstrating an incongruent effect characteristic of this subtype. Hebephrenic schizophrenia usually develops between the ages of 15-25 and can only be diagnosed if the onset is within this age range. They carry a poorer prognosis compared to other forms of schizophrenia due to the rapid development of negative symptoms. Hallucinations and delusions may be present but are not normally prominent. A period of observation over 2-3 months is essential in making the diagnosis.

Catatonic schizophrenia 

This form of schizophrenia is now relatively uncommon in Western countries. Classically, patients demonstrate a marked change in motor function. This can include: stupor (marked reduction in reactivity to environment, spontaneous movements and activity), mutism, rigidity (stiff, immobile posture that cannot be moved by someone else), waxy flexibility (maintenance of limbs and body in a position created by someone else), command automation (immediately following the commands of someone else) and perseveration (repetition of a response, gesture, or phrase). Although the term catatonic reflects the hypoactive behaviours characteristic of this subtype, individuals can show periodic hyperactive behaviour, often alternating between the two. In patients with catatonic schizophrenia, it is especially important to monitor their physical health as they can become malnourished due to prolonged catatonic states.

Undifferentiated schizophrenia 

The category is reserved for patients that meet the diagnostic criteria for schizophrenia and either fail to meet the specific criteria for one specific subtype, or they have multiple symptoms qualifying for more than one subtype.

Residual schizophrenia 

This diagnosis applies to individuals who have had at least one clear-cut episode of active schizophrenia and continue to present with symptoms to a much lesser extent. Often, the positive symptoms, such as delusions and hallucinations, are markedly reduced, whereas negative symptoms, such as blunted affect, poverty of speech and psychomotor retardation continue to persist.

Simple schizophrenia 

This is a fairly uncommon disorder with an insidious onset. The individual demonstrates a progressive development of negative symptoms by becoming more blunted in affect, loss of drive and interest, paucity of speech and passivity, which leads to a marked decline in social, occupational, or educational performance. It is important to note that these individuals will not have experienced any psychotic symptoms such as delusions or hallucinations and do not meet the criteria for any of the other schizophrenia subtypes.

Post schizophrenic depression 

In this subcategory, the individual meets the diagnostic criteria for schizophrenia and has had an acute episode within the last 12 months. Some of the symptoms are still present (most often the negative symptoms), as they begin to experience low mood symptoms that are more prominent than the schizophrenic symptoms. The low mood symptoms must be present for a minimum of two weeks. If the individual no longer has any schizophrenic symptoms, then the diagnosis is now depression, whereas if the schizophrenic symptoms are still present and more prominent than the low mood symptoms, then the diagnosis of the schizophrenic subtype should persist.

Differential diagnoses

  • Schizophreniform disorder:  all the criteria for Schizophrenia are present for at least one month but less than 6 months in total. Social and interpersonal functioning is affected to a lesser extent compared to Schizophrenia.
  • Schizoaffective disorder: The affective symptoms (e.g. depression or mania) and schizophrenic symptoms are present to an equal degree such that it is difficult to distinguish which is more prominent to make a singular diagnosis.
  • Psychotic mood disorders: e.g. Mania with psychosis or depression with psychosis. There are prominent mood symptoms (e.g. major depression or mania) in addition to psychotic symptoms such as delusions or hallucinations. You can distinguish Psychotic mood disorders from Schizoaffective disorder based on the timing of the symptoms. In schizoaffective disorder, psychosis is present in the absence of the mood component, whereas, in the alternative, psychosis is present and driven by the significant mood change.
  • Substance-induced psychotic disorder: e.g. ketamine, cocaine, amphetamine. Symptoms manifest during the acute period of drug use or alcohol withdrawal and do not persist when the individual is sober.
  • Persistent Delusional disorder: the individual has a firm, fixed delusion (for at least 1-month duration) in the absence of other psychotic symptoms such as hallucinations and continues to have adequate social functioning. In addition, the individual should not meet the criteria for an alternative diagnosis.
  • Organic causes: Psychosis can occur secondary to a medical condition. It is, therefore, important to ensure a thorough history, including a collateral history, is taken to ensure accurate chronology of symptomology and differentials are considered. Listed below are some medical conditions that can cause psychosis.
    • Delirium
    • Intracranial tumours: occipital or temporal lobe tumours are associated with hallucinations, whereas tumours in the parietal and temporal lobe are more associated with delusions
    • Metabolic disorders: Wilson’s disease
    • Infectious disease: encephalitis
    • Hepato-renal disorders: hepatic encephalopathy, uraemic encephalopathy
    • Neurodegenerative disease: Alzheimer’s, Huntington’s disease, Lewy body dementia

References

Management

All patients with an acute episode of Schizophrenia should be started on antipsychotic medications to minimise their symptoms, induce remission and return them to normal functioning. The choice of antipsychotic should follow a discussion with the patient regarding current symptoms, side effects and alternative treatments. The management plan should follow the ‘BioPsychoSocial’ model.

  • Biological: Drug therapy
  • Psychological: supportive therapy, cognitive behavioural therapy, family therapy
  • Social: Avoid drugs/alcohol, increase social support (Community Psychiatric Nurse support), stable housing, financial support and employment

There are two classes of antipsychotics commonly used in schizophrenia: First-Generation Antipsychotics (FGA) and Second-Generation Antipsychotics (SGA). In recent years, SGA has been the preferred choice due to carrying a lower risk of extrapyramidal side effects; however, there is no difference noted between the efficacy of FGA and SGA in treatment of negative and cognitive symptoms of schizophrenia (aside from Clozapine). An antipsychotic should be trialled for a minimum of four weeks before considering alternative options due to poor response.

First-Generation Antipsychotics (FGAs)

FGAs are primarily dopamine antagonists, blocking the action of dopamine on its receptors throughout the brain. One of the theoretical causes of schizophrenia is excess dopamine in the mesolimbic pathways, which is associated with positive symptoms; hence, blocking this pathway aids in alleviating positive symptoms like hallucinations and delusions. However, FGAs are not specific to D2 receptors and exhibit their action on a number of other receptors, resulting in a varied side effect profile. This includes exerting antagonism at Acetylcholine ACh M1, Histamine H1 antagonist and a1-adrenergic receptors.
Effect of First-Generation Antipsychotics on D2 receptors
D2 receptor in mesolimbic pathway D2 receptor in Nigrostriatal Pathway D2 receptor in tuberoinfundibular pathway (hypothalamus/pituitary)
  • Antagonistic action
  • Reduction in positive symptoms; reduced hallucinations, delusions
  • Antagonistic action
  • Extrapyramidal symptoms
  • Tardive dyskinesia: abnormal, asymmetric movements of face, tongue or limbs
  • Drug-induced parkinsonism: cogwheel rigidity, resting tremor, bradykinesia, akathisia
  • Acute dystonia: muscular spasm of neck, eye, tongue/jaw
  • Akathisia: motor restlessness
  • Antagonistic action
  • Loss of pituitary gland inhibition leading to prolactin secretion resulting in Hyperprolactinaemia
  • Amenorrhea, galactorrhoea, loss of sexual function, reduced pubic hair
Additional receptor profile of First Generation Antipsychotic
Muscarinic Histamine Adrenergic
  • Antagonistic action
  • Dry mouth
  • Constipation
  • Blurred vision
  • Cognitive slowing
  • Antagonistic action
  • Weight gain
  • Drowsiness
  • Antagonistic action
  • Orthostatic hypotension

Source: Adapted from: UpToDate. First Generation Antipsychotic Medications: Pharmacology, administration and comparative side effects [internet]. 2022 [cited 2022 July 15]. Available from: https://www.uptodate.com/contents/first-generation-antipsychotic-medications-pharmacology-administration-and-comparative-side-effects

Second-Generation Antipsychotics (SGAs)

Similarly to FGAs, SGAs have their mode of action on D2 receptor antagonists as well as 5-HT2A (Serotonin) receptors. SGAs have a higher affinity for 5-HT2A (Serotonin) receptors than D2 receptors, thereby exhibiting fewer extrapyramidal side effects. However, compared with FGAs, SGAs’ have a higher risk of metabolic side effects leading to metabolic syndrome. This can lead to increased risk of HTN, diabetes and cardiovascular complications.

MRCP Part 1 - Pyramid illustrating factors contributing to Metabolic syndrome

Source: Adapted from: National Health Service. Metabolic syndrome [internet]. 2019 [cited 2022 July 15]. Available from: https://www.nhs.uk/conditions/metabolic-syndrome/
Individual risks of Antipsychotics
First generation antipsychotics Second generation antipsychotics
Phenothiazine:

e.g. chlorpromazine, promazine, trifluoperazine (drowsiness, dry mouth ++)

Butyrophenones:

e.g. haloperidol (Tardive Dyskinesia +)

Thioxanthenes:

Flupenthixol, zuclopenthixol, clopenthixol

Higher rates of Extrapyramidal side effects

 Olanzapine (Weight gain ++)

Risperidone (hyperprolactinaemia ++)

Paliperidone (hyperprolactinaemia ++)

Aripiprazole (low doses can be used to lower prolactin levels)

Quetiapine (weight gain ++)

Amisulpride (hyperprolactinaemia ++)

Clozapine (agranulocytosis ++)

High risk of metabolic syndrome

Source: Adapted from: National Institute for Health and Care Excellence. Psychoses and related disorders [internet]. [cited 2022 July 15]. Available from: https://bnf.nice.org.uk/treatment-summaries/psychoses-and-related-disorders/

Clozapine 

Indication

Clozapine is an atypical antipsychotic that is reserved for use in treatment-resistant schizophrenia. It has also been shown to be efficacious against negative schizophrenic symptoms, suicidal and self-harm symptoms. Other indications for clozapine include intolerance to typical or atypical antipsychotics due to extrapyramidal side effects or tardive dyskinesia.

Clozapine drug monitoring

Clozapine is an expensive medication to prescribe, partly due to the fact that it requires intense monitoring via regular blood tests, physical health monitoring and strict regulation on dispensing. The diligent supervision of Clozapine is due to the potentially fatal risk of agranulocytosis. Prior to initiation, the individual must have an FBC to rule out pre-existing haematological disorders (particularly neutropenia). This is then followed by weekly blood tests for 18 weeks, then fortnightly for up to one year. Once stabilised, the frequency of blood tests is reduced to monthly.

Blood test results are reported using a traffic light system.

Green: WBC>3.5, Neutrophils >2.0

Amber: WBC 3.0-3.5, Neutrophils 1.5-2.0

Red: WBC <3.0, Neutrophils <1.5

A green result indicates that the neutrophils are within range, so the patient can continue to take their medication as normal. An amber result should be acted upon with increased blood test monitoring (twice weekly). The clinician (Consultant Psychiatrist) will need to assess the situation and investigate any causative factors that may have contributed to this result, such as concomitant immunosuppressive treatment for another condition, before making a decision regarding a reduction in the treatment dose. If a Red result occurs, then Clozapine will need to be stopped IMMEDIATELY. The patient’s blood counts are low enough to significantly increase their risk of infection and sepsis. Restarting Clozapine following a red result is not straightforward, even if subsequent green results have been obtained. A multidisciplinary team will need to be involved in this decision-making process, weighing up the risks and benefits for each individual patient. It may require re-trialling other antipsychotics before testing it once more.

References

Prognosis

There is currently no singular cure known to treat schizophrenia; with complete resolution being relatively uncommon. A small proportion of patients may have only a singular episode throughout their lifetime, whereas others will have either recurrent episodes or continuous symptoms. A few factors are known to influence the longitudinal trajectory of the illness and can be used to somewhat predict how an individual will be affected. Factors such as prominent negative symptoms are notoriously difficult to treat, as most antipsychotics have greater efficacy in treating positive symptoms than negative symptoms. Of course, this will be different for each patient individually, but it is worth bearing these prognostic factors in mind so they can be addressed in a patient’s treatment plan, when feasible.

Good Prognosis Poor Prognosis
Late-onset Young-onset
Acute onset No precipitating factors
Good premorbid social functioning (employed, social network) and support systems Poor premorbid social functioning (unemployed, no social network), no support system
Married Single or divorced
Family history of mood disorder Family history of schizophrenia
Positive symptoms Negative symptoms

Multiple relapses

Continuous symptoms (no remissions)

Source: Adapted from:  Saddock J, Saddock V. Concise textbook of clinical psychiatry. 3rd ed. Philadelphia: Wolters Kluwer; 2008.

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