Schizophrenia

• 

   Pathophysiology and epidemiology

  Dopamine theory:

  • Overactive dopamine system, especially in the mesolimbic area, causes the positive symptoms of schizophrenia.

  Associated brain changes:

  • Larger lateral ventricles.
  • Reduced volume of the frontal lobe, parahippocampal gyrus, hippocampus, temporal lobe, and/or amygdala.
  • None of these changes are especially sensitive or specific.

  Epidemiology:

  • 0.5% lifetime risk.

• Presentation

  Signs and symptoms

  Positive symptoms:

  • Hallucinations: commonly auditory. Usually in the 3rd person but can be 2nd person. May include thought echo, running commentary, or overheard conversations.
  • Delusions: persecutory, reference, interference, passivity.
  • Thought disorder: derailment, poverty, circumstantiality, perseveration, blocking.

  Negative symptoms:

  • Apathy
  • Self-neglect
  • Paucity of speech.
  • Social withdrawal.
  • Emotional blunting.
  • Anhedonia

  First-rank symptoms:

  • A group of symptoms which are common and easy to identify. Individually not very sensitive, but all fairly specific for schizophrenia.
  • They are: auditory hallucinations, thought interference, delusions of control, and delusional perceptions.

  Prodrome:

  • Social withdrawal.
  • ↓Function e.g. in work or studies.
  • Eccentricity, including odd speech, perceptions, or ideas.
  • Poor self care.
  • Low mood or blunted affect.

  ICD-10 criteria

  Symptoms must last >1 month.

  Any 1 of:

  • Thought echo.
  • Thought alienation: insertion, withdrawal, or broadcasting.
  • Delusions of control, influence, or passivity, with clear effect on actions, sensations, or feelings.
  • Any other persistent delusion e.g. grandiosity.
  • Delusional perceptions.
  • Auditory hallucinations.

  Or any 2 of:

  • Any other persistent hallucination or overvalued idea.
  • Breaks in thought leading to incoherence in speech.
  • Catatonic behaviour: excitement, waxy flexibility, negativism, mutism, or stupor.
  • Negative symptoms.

• Risk factors

  • Family history.
  • Perinatal: in-utero viral infection, hypoxic birth injury.
  • Economic: urban living, ↓socio-economic status.
  • Race: immigrants, non-white.

• DDx: Psychosis

  Defined as loss of contact with reality, manifest in delusions, hallucinations, thought disorder, and a lack of insight.

  Psychiatric causes:

  • Schizophrenia
  • Mood disorders: bipolar disorder, severe depression, schizoaffective disorder.
  • Delusional disorder.
  • Transient psychosis.

  Organic causes:

  • Neurodegenerative: dementia, Parkinson's disease or medication for it.
  • Structural: space-occupying lesions, temporal lobe epilepsy.
  • Acute: delirium, encephalitis.
  • Endocrine: thyrotoxicosis, post-partum psychosis.

  Medicine:

  • Steroids
  • Anti-malarials

  Recreational drugs:

  • Alcohol and alcohol withdrawal (delirium tremens).
  • Cocaine
  • Cannabis
  • Amphetamines
  • Hallucinogens e.g. psilocybin.

• Investigations

  Assessment should be carried out by a psychiatrist or other trained specialist, and include:

  • Full history and MSE.
  • Neurological examination.
  • Collateral history.

  Investigate differentials if indicated:

  • Endocrine: TFT, cortisol.
  • Infectious: syphilis serology, HIV.
  • Urine drug screen: can detect cannabis for weeks or even months after cessation. Commonly also checks for opioids, cocaine, and amphetamines.
  • Neurological: CT/MRI brain, LP, EEG.

• Management

  Basics:

  • Follow a bio-psycho-social approach.
  • New patients should be offered a full MDT assessment in secondary care, addressing psychiatric, physical, psychological, social, and economic needs.
  • Ideally, those with a first episode of psychosis or at risk of psychosis should be referred to an early intervention in psychosis (EIP) team, regardless of their age or symptom duration. EIP can offer the full range of treatments.
  • Write a care plan in collaboration with the patient.
  • If the patient is stable after 1 year on antipsychotics, they can be looked after in primary care.

  Biological: antipsychotics

  Drug choice and initiation:

  • 1st line: oral (ideally) or depot, 1st or 2nd generation antipsychotic. If one fails, switch to another, at least one of which should be 2nd generation.
  • 2nd line: clozapine is the only one which is more effective than the others, but has more side effects. Offer if 2 different antipsychotics were ineffective, which happens in 20% of patients.
  • Depot drugs if there is poor adherence. Options are olanzapine, risperidone, haloperidol, fluphenazine, flupentixol, or zuclopenthixol.
  • Start low and titrate up, then observe effectiveness for 4-6 weeks at optimum dose.
  • Avoid combination treatment, except perhaps for overlap periods when switching. It can also be considered if patients have not adequately responded to clozapine alone.

  Basic tests at baseline and annual check up:

  • Basic bloods: FBC, U&E, LFTs.
  • Metabolic syndrome and cardiovascular monitoring: fasting glucose, HbA1c, lipids, weight, waist circumference, BP, ECG.
  • PRL

  Additional monitoring:

  • Weight: weekly for first 6 weeks, then at 3 months.
  • BP, HR, lipids, and glucose at 3 months, and PRL at 6 months.
  • Continued ECG monitoring for haloperidol and pimozide.
  • Continued FBC monitoring for clozapine. Weekly for first 18 weeks, and then less frequently. In patients with poor health, treatment should be initiated and titrated in hospital.

  Psychological

  Psychological therapy should be offered in combination with antipsychotics:

  • Individual CBT: 16 sessions, focusing on re-evaluating abnormal thoughts and perceptions, and reducing the distress resulting from symptoms.
  • Family intervention should also be offered, ideally including the patient and involving at least 10 sessions over 3-12 months. Consists of psychoeducation (e.g. how to respond to patient's delusions), advice on crisis management, and emphasizing the importance of creating low stress environments at home.
  • Art therapy is another option. It can help with self-expression, and is delivered in groups, thus alleviating social isolation.
  • These treatments can be started in the acute phase or later.

  Preventing psychosis in those at risk:

  • Signs of being at risk: distress and impaired social functioning, plus transient/mild psychosis or a 1st degree relative with psychosis. Do not meet criteria for schizophrenia.
  • Offer CBT ± family intervention.
  • Do not offer antipsychotics.
  • Continue to monitor closely until they improve or develop a clear psychotic illness.

  Social

  Basics:

  • Offer a healthy eating and physical activity programme, especially if on antipsychotics.
  • Assist in getting mainstream education, work or training, and offer alternative specialist services if this is not possible.
  • Peer support: given by recovered and stable patients who have had schizophrenia or psychosis.
  • Refer to day centres to help with social isolation.

  Encourage smoking cessation:

  • Offer nicotine replacement, bupropion, or varenicline.
  • Serum antipsychotic levels often increase after cessation as smoking increases antipsychotic metabolism. Monitor patients carefully during this time, and consider dose reduction if necessary.

  Support carers:

  • Offer a formal assessment of their needs by mental health services, and provide support as needed.
  • Discuss with patient what information-sharing they are happy with.

• Complications and prognosis

  Complications:

  • Drug use
  • Risk of criminal victimization, including violence.
  • Suicide
  • Early death from medication side effects.

  Prognosis:

  • 30% recover.
  • 50% follow a relapsing-remitting course.
  • 20% are chronically incapacitated.

  Bad prognostic factors:

  • Early or insidious onset.
  • Continued exposure to precipitants.
  • Family history of schizophrenia or mood disorder, or family members with high expressed emotion.
  • Negative symptoms or affective elements.
  • ↓IQ

• First-generation antipsychotics

  Drugs

  • Oral: chlorpromazine, haloperidol, trifluoperazine, sulpiride, pimozide, prochlorperazine, levomepromazine.
  • Depot: haloperidol, fluphenazine, flupentixol, zuclopenthixol.

  Mechanism

  • Dopamine D2 receptor blockers.

  Extra-pyramidal side effects (EPSE)

  Features:

  • Parkinsonism
  • Tardive dyskinesia: lip smacking, rocking, rotating ankles, marching in place, repetitive sounds. Happens with chronic use, hence 'tardive' i.e. late, delayed-onset. Treat with tetrabenazine, a monoamine uptake inhibitor.
  • Akathisia: an inner state of restlessness. Carries increased risk of suicide.
  • Acute dystonia: painful, sustained muscle spasm, especially of neck (torticollis), jaw, or eyes. Treat with procyclidine or benztropine.

  Frequency vs. second generation antipsychotics (SGA):

  • While first-generation antipsychotics (FGA) were traditionally thought to have greater EPSE than SGA, this was only consistently shown for haloperidol, while lower-potency FGA appear no worse than SGA.
  • It is also worth noting that prophylactic benztropine mitigates the increased EPSE in haloperidol, and haloperidol causes less weight gain than SGA.

  Other side effects

  • ↑Prolactin, as dopamine inhibits its release.
  • Sedation – especially the anti-histaminergic phenothiazines (chlorpromazine, prochlorperazine) – and apathy.
  • Metabolic syndrome, ↑weight, and T2DM. Stroke and VTE risk in elderly.
  • Anticholinergic effects.
  • Postural ↓BP, especially chlorpromazine.
  • Photosensitivity with chlorpromazine.
  • Long QT: especially haloperidol and pimozide.
  • Sexual dysfunction, especially haloperidol, due to ↓dopamine and ↑PRL.
  • Neuroleptic malignant syndrome.
  • Many of these – EPSE, sedation, ↑weight, and anticholinergic effects – are lower with sulpiride.

• Second-generation antipsychotics

  Drugs

  • Oral: amisulpiride, aripiprazole, clozapine, olanzapine, risperidone, quetiapine.
  • Depot: olanzapine, risperidone.

  Mechanism

  • More selective blockade of certain D2 receptors.
  • Also block 5-HT receptors.

  Side effects

  • Traditionally thought to have fewer extra-pyramidal side effects than first generation antipsychotics, but they can still occur, especially with risperidone.
  • Sedation and apathy.
  • Metabolic syndrome, ↑weight, and T2DM, especially clozapine and olanzapine. Stroke and VTE risk in elderly.
  • ↑Prolactin, especially amisulpiride and risperidone.
  • Sexual dysfunction, especially risperidone.
  • ↑QT, especially quetiapine.
  • Neuroleptic malignant syndrome.
  • Aripiprazole has a lower risk of many side effects, including sedation and metabolic syndrome. It also lowers PRL, so should be considered if this is raised by another antipsychotic.

  Clozapine

  • Most effective but 'dirtiest' antipsychotic, with lots of side effects.
  • Common side effects: sedation, metabolic syndrome, ↓BP, anti-cholinergic effects. Paradoxically, can also cause hypersalivation, which may need to be treated with an anti-cholinergic such as hyoscine hydrobromide.
  • Agranulocytosis, especially neutropenia, is a rare but severe side effect. Clozapine therefore requires FBC monitoring.
  • Constipation is relatively common. In rare cases, it can be a severe and life-threatening paralytic ileus.
  • Levels may jump suddenly after smoking cessation, so look out for side effects.

• Neuroleptic malignant syndrome

  Severe, rare side-effect of antipsychotics with 10% mortality.

  Pathophysiology

  Mechanism unclear, but may relate to hypothalamic dopaminergic blockade causing hyperthemia and dysautonomia.

  Presentation

  Usually develops in first 2 weeks of antipsychotic use, but can occur any time.

  Classic tetrad, HARD:

  • Hyperthermia
  • Altered mental status.
  • Muscle Rigidity, generalized. Associated ↑CK.
  • Dysautonomia: ↑HR, labile BP, sweating.

  Management

  • Discontinue antipsychotic. Symptoms usually continue for 5-10 days.
  • Bromocriptine (dopamine agonist) and/or dantrolene (muscle relaxant) are sometimes used, but evidence is very limited.
  • If still indicated, wait at least 2 weeks before re-starting antipsychotic, with low dose and cautious titration.

• Schizophrenia sub-types

  Paranoid schizophrenia

  • Commonest type.
  • Complex delusions and hallucinations, often of persecutory, grandiose, and/or religious nature.

  Hebephrenic schizophrenia

  • Inappropriate mood and behaviour including silliness, shallowness, and irresponsible actions.
  • Fragmented delusions and/or hallucinations.
  • Poor prognosis.

  Catatonic schizoprhenia

  • Psychomotor disturbance including stupor, outbursts, waxy flexibility, automatic obedience, and negativism.

  Simple schizoprhenia

  • Negative symptoms dominate.
  • May just consist of a significant and consistent change in some aspect of behaviour e.g. loss of interest, aimlessness, idleness, social withdrawal.