Antipsychotic Medications

Antipsychotics can be categorised as typical and atypical. Typical antipsychotics were developed first, and are associated with a greater risk of extrapyramidal side effects. 

Typical (first generation) Antipsychotics

Examples

  • Haloperidol, Chlorpromazine 

Mechanism of action

  • Dopamine (D2) Receptor Antagonists 

Important side effects

  • Hyperprolactinaemia - oligo-/amenorrhoea, loss of libido and erectile dysfunction, galactorrhoea
    • Remember - dopamine inhibits prolactin release
  • Extrapyramidal side effects - parkinsonism, dystonias, akathisia, tardive dyskinesia 
  • Antimuscarinic effects - dry mouth, blurred vision, urinary retention, constipation
  • Impaired glucose tolerance
  • Reduced seizure threshold - caution in patients with epilepsy

 

Extrapyramidal side effects

Drug induced parkinsonism

  • Classically of rapid onset and features are symmetrical.
    • Unlike IPD - symptoms are of gradual onset, and typically asymmetrical

Akathisia

  • A feeling of severe restlessness

Tardive Dyskinesia

  • Involuntary, slow writhing movements 
  • Classical movements include chewing, grimacing, tongue protrusion, lip smacking. 

Dystonias 

  • Sustained muscle contractions - oculogyric crisis / torticolis 
    • Torticolis - also referred to as 'wry neck' - severe neck muscle spasm/contraction resulting in involuntary head tilting
    • Oculogyric Crisis - involuntary, extreme upward deviation of gaze +/- the presence of torticolis, tongue protrusion, jaw spasm
  • Management of acute dystonias: Procyclidine (anticholinergic) or Benzatropine 

 

Other complications of typical antipsychotics

  • Typical APs should be prescribed with caution in elderly patients, increasing the risk of stroke and DVT/PE. 
  • Neuroleptic Malignant Syndrome - see below
  • Polymorphic VT/ Torsades de pointes - due to prolongation of the QTc (esp. with haloperidol)


 

Atypical (second generation) Antipsychotics

Atypical antipsychotics are first line in schizophrenia

Mechanism of action

  • Act on a wider variety of receptors (D2, D3, D4, 5-HT)

Examples 

  • Olanzapine
  • Risperidone
  • Aripiprazole
  • Quetiapine
  • Clozapine
  • Amisulpride

Advantages

  • Lower risk of extrapyramidal side effects (EPSEs) vs typical APs

Side effects

  • Metabolic syndrome -  weight gain, insulin resistance/diabetes, dyslipidemia - therefore associated with accelerated cardiovascular disease. 
  • Stroke and VTE (esp in elderly patients)
  • EPSEs + hyperprolactinemia - less common

 

Clozapine

  • Clozapine is indicated in the management of schizophrenia, if symptoms are not adequately controlled despite the use of 2 or more antipsychotics for 6-8 weeks. This is due to its association with significant adverse effects, which include:
    • Agranulocytosis - FBC monitoring is essential 
    • Seizures
    • Myocarditis - a baseline ECG is required before commencing treatment
    • Constipation
    • Clozapine induced Hypersalivation - a significant side effect, affecting approximately 1/3rd of patients.
      • Hyoscine butylbromide can be prescribed to relieve hypersalivation

  

Neuroleptic Malignant Syndrome (NMS)

A known complication associated with the use of antipsychotics. NMS can also be triggered by missed doses of levodopa/parkinson’s meds. 

Clinical features

  • Pyrexia
  • Muscle rigidity
  • Agitation and delirium 
  • Autonomic lability - Hypertension and tachycardia

Examination findings

  • Reduced or absent reflexes
  • Normal pupils
  • Differential diagnosis - serotonin syndrome - characterised by dilated pupils, myoclonus and brisk reflexes. 

Complications

  • Rhabdomyolysis and resultant AKI

Management

  • Stop antipsychotics 
  • IV fluids
  • Dantrolene 
  • Bromocriptine/ dopamine agonists may be beneficial

 

 

Antidepressants

 

Selective Serotonin Reuptake Inhibitors (SSRIs)

Mechanism of action

  • Increase the extracellular levels of the neurotransmitter serotonin, by inhibiting its reuptake into the presynaptic cell.

Examples

  • Sertraline
  • Fluoxetine
  • Citalopram

Contraindications (NICE)

  • Current mania
  • Poorly controlled epilepsy 
  • Avoid citalopram/escitalopram if QT prolongation or in combination with other drugs which increase the QTc - risk of TDP
  • Avoid sertraline in severe hepatic impairment 

SSRIs in cardiovascular disease

  • Sertraline is safest

Side effects of SSRIs

  • Gastrointestinal side effects are the most common
  • Consider PPI co-prescription (e.g. if on NSAIDs)

Interactions/contraindications

  • Use with caution with aspirin or NSAIDs – increased risk of PUD/GI bleed
  • Avoid with warfarin or heparin due to bleeding risk – give mirtazapine instead
  • Avoid co-prescribing triptans or MAOIs – risk of serotonin syndrome

Follow up

  • Patients should be followed up shortly after commencing SSRIs due to the risk of increased anxiety and suicidal ideation
  • If < 30 years of age, follow patients up in 1 week
  • If > 30 years – follow up in 2 weeks

Stopping SSRIs

  • If patients show a good response, they should continue SSRIs for at least another 6 months before discontinuation, or there is a high risk of symptom relapse. 
  • Stopping SSRIs suddenly can result in high risk of discontinuation syndrome 
    • Clinical features: restlessness, anxiety and agitation, GI symptoms (diarrhoea etc.)
    • Gradually reduce dose over 4 weeks before stopping to reduce this risk
    • Paroxetine - highest risk of discontinuation syndrome

 

Serotonin Syndrome

Causes

The following drugs are associated with serotonin syndrome, particularly if co-prescribed/ingested: 

  • SSRIs
  • MAOIs
  • Triptans
  • Ecstasy/methamphetamines
  • St Johns Wort. 

Clinical Features

  • Neuromuscular excitation: Increased reflexes, myoclonus, rigidity
  • Autonomic lability – tachycardia, hypertension, pyrexia
  • Confusion, agitation, aggression
  • Note: Myoclonus is a useful differentiating feature from neuroleptic malignant syndrome 

Management 

  • IV fluids
  • Benzodiazepines – the mainstay of management
  • In severe serotonin syndrome – cyproheptadine or chlorpromazine can be used  (serotonin antagonists)

 

SNRIs

Mechanism of action

  • Serotonin + noradrenaline reuptake inhibitors – increased levels of neurotransmitters at the synaptic cleft

Examples

  • Venlafaxine
  • Duloxetine

 

Monoamine oxidase inhibitors (MAOIs)

Mechanism of action

  • Reduce metabolism of serotonin and noradrenaline in the presynaptic clefts)

Examples

  • Phenelzine 

Side effects

  • MAOIs are associated with hypertension particularly if used whilst tyramine containing foods are eaten (cheese, herring, broad beans)

 

Tricyclic Antidepressants

An old class of antidepressants which have a number of additional uses. For example, amitriptyline is used in the management of neuropathic pain & migraine prophylaxis. 

Adverse effects

  • Antimuscarinic effects – dry mouth, constipation, urinary retention, blurred vision
  • Drowsiness
  • Prolongation of the QTc (risk of TDP)

TCAs in overdose

TCAs are considered the most dangerous antidepressants in overdose (esp. Amitriptyline and dosulepin)

Clinical features

  • Drowsiness
  • Dry mouth, blurred vision
  • Pupils - dilated
  • Arrhythmias
  • Seizures
  • Metabolic acidosis
  • Coma 
  • ECG: Long QTc interval, widened QRS, tachycardia – broad complex tachyarrhythmia with long qt. 

Management

  • IV Sodium Bicarbonate is the mainstay of management – indications include widened QRS > 100 or ventricular arrhythmia

  

 

Benzodiazepines

Mechanism of action

  • Increase frequency of chloride channel transmission – increase effects of GABA

Discontinuation

  • Withdraw benzodiazepines in steps of 1/8th at a time, every few weeks

Clinical Features of BZD withdrawal

  • Anxiety, tremor, irritability, tinnitus, sweating and seizures – last up to 3 weeks after last dose. 

   

 

Lithium

Lithium is a mood stabiliser, commonly used in the management of bipolar affective disorder (BAD)

Side effects/complications

  • Nausea and vomiting
  • Fine tremor (a coarse tremor suggests toxicity)
  • Nephrogenic diabetes insipidus
  • Hypothyroidism
  • Weight gain
  • IIH
  • Hyperparathyroidism and hypercalcaemia

Monitoring

  • Lithium levels - measure one week after starting treatment and one week after making any adjustments to dose. Once stable, check 3 monthly.
  • 6 monthly - BMI, UE, Calcium, TFTs
    • If urea/cr increases or eGFR decreases, measure lithium levels more frequently than 3 monthly as higher risk of toxicity.