Tardive and Neuroleptic-induced Emergencies

Mir Ali Raza Talpur, M.D1 , Danish Bhatti M.D2

1 Liaquat National Hospital and Medical College, Pakistan.

2 Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE

Introduction

  • Antipsychotics are a group of drugs used primarily to treat psychosis, schizophrenia, mania and agitation.
  • There are two types/classes of antipsychotic drugs being used in the meantime: First Generation Antipsychotics (FGAs), also known as Typical Antipsychotics and Second Generation Antipsychotics (SGAs), also known as Atypical Antipsychotics.
  • The antipsychotic effect of FGAs (e.g. haloperidol) is Dopamine (D2) receptor antagonism, while SGAs interact with several receptors (e.g. Dopamine, Alpha-Adrenergic, Histamine and Serotonin receptors).
  • Extrapyramidal symptoms, which include acute dystonia, akathisia, pseudoparkinsonism and tardive dyskinesia, are the most common side effects of first-generation antipsychotics, but can also occur with second-generation antipsychotics.
  • Metabolic side effects (e.g., weight gain, hyperglycemia, dyslipidemia) are more common with second-generation antipsychotics, but also occur with first-generation antipsychotics.

Overview of Antipsychotics

  • First Generation Antipsychotics - Typical Antipsychotics
    • Mechanism of action
    • Post-synaptic blockade of dopamine (D2) receptors in the central nervous system.
    • Low potency antipsychotics also antagonize cholinergic and histaminergic receptors along with dopamine receptor antagonism.
  • Adverse effects
    • Hyperprolactinemia.
    • Prolonged QT interval.
    • Neuroleptic malignant syndrome.
    • Extrapyramidal symptoms (more common with high potency drugs).
    • Anticholinergic effects
      • Dry mouth
      • Blurred vision
      • Mydriasis
      • Constipation
      • Urinary retention
      • Tachycardia.
    • Sedation.
    • Sympatholytic effects (e.g, orthostatic hypotension).
    • Metabolic effects
      • Weight gain
      • Hyperglycemia
      • Dyslipidemia
  • Second generation antipsychotics - Atypical Antipsychotics:
    • Mechanism of action
      • Transiently inhibit dopamine receptors.
      • Also have antagonizing effects on serotonergic (5HT2A), cholinergic, alpha adrenergic and histaminergic receptors.
      • Aripiprazole is partial D2 receptor agonist.
    • Adverse effects
      • Metabolic effects
        • Weight gain
        • Hyperglycemia
        • Dyslipidemia
      • Sedation, somnolence
      • Prolonged QT interval
      • Anticholinergic effects
        • Dry mouth
        • Blurred vision
        • Mydriasis
        • Constipation
        • Urinary retention
        • Tachycardia
      • Sympatholytic effects (e.g, orthostatic hypotension)
      • Neuroleptic malignant syndrome
      • Clozapine causes agranulocytosis
      • Hyperprolactinemia and extrapyramidal symptoms which are less common than first generation antipsychotics

Table 1: First Generation Antipsychotics

Table 2: Second Generation Antipsychotics

Epidemiology

  • Antipsychotics are one of the top 5 drug classes prescribed worldwide.
  • First Generation Antipsychotics were introduced in the 1950s.
  • Second Generation Antibiotics were later introduced in the 1980s.
  • By early 2000s, more than 90% of the antipsychotics prescribed to new users were second generation.
  • The major goal to prescribe second generations was to decrease the incidence of extrapyramidal symptoms and hyperprolactinemia, which were a major concern with first generation antipsychotics.
  • Mortality is rare with antipsychotic medications but can increase up to 10-12% if Neuroleptic Malignant Syndrome develops.
  • Using multiple antipsychotic drugs in combination may result in increased toxicity if taken carelessly or more than a prescribed dose.
  • An increased incidence of toxicity is sometimes seen in elderly patients.

Drug Induced Emergencies

Extra Pyramidal Symptoms (EPS)

    • A set of movement disorders that results in bradykinesia, athetosis, akathisia, rigidity, ballismus, tics and tremors etc
    • Pathophysiology includes inhibition of nigrostriatal dopaminergic pathways in the brain.
    • All the antipsychotics that interact with D2 receptors can cause EPS, more specifically, High Potency FGAs (e.g, Haloperidol)..
    • Following are few subtypes of EPS:
      • Acute Dystonias
        • Involuntary and prolonged, painful muscle contractions.
        • Occurs typically within few hours to days.
        • Typically occurs after initiating a drug or during dose adjustments.
        • Risk factors:
          • Male gender
          • Young age
          • History of dystonia
          • Recent cocaine use
        • Typically involves face, head, tongue, neck and back.
          • Tongue twisting or protrusion
          • Facial grimacing
          • Opisthotonus of the back
          • Oculogyric crisis ( upward deviation of eyes)
          • Torticollis crisis
          • Laryngeal dystonia
          • Pseudo macroglossia
        • Acute treatment includes anticholinergic drugs or antihistamines
          • First line: IV/IM Benztropine 1-2 mg.
          • Second line:
            • IV/IM Diphenhydramine 25-50 mg and IV 1 mg/kg in pediatric patients.
            • Benzodiazepines, e.g, IV/IM Lorazepam 0.05-0.10 mg/kg. IV Diazepam 0.1 mg/kg.
          • Airway management with intubation (ICU Protocol) if severe laryngeal compromise.
        • Long term treatment involves switching to Second generation antipsychotics .
        • Prophylaxis with Benztropine or Diphenhydramine involves patients who receive intramuscular Haloperidol.
      • Akathisia
        • Compelling urge to move or restlessness.
        • Inability to sit or stand still.
        • Pathophysiology involves imbalance between cholinergic/dopaminergic or serotonergic/dopaminergic systems in nucleus accumbens.
        • Occurs within weeks 1-8 of the initiation of drug and may last several months, or sometimes even years.
        • To assess the severity, clinicians may use tool known as Barnes Akathisia Rating Scale (BARS).
        • Akathisia is associated with the increased risk of anxiety and dysphoria, which results in patients being suicidal or opting self-harm behaviour.
        • Acute treatment:
          • First line:
            • Oral Propranolol 40-80 mg daily.
            • Oral Diazepam 5-15 mg daily.
            • Oral Clonazepam 0.5-1 mg daily.
          • Second line: Oral Benztropine 1-4 mg daily (if concomitant pseudoparkinsonism present).
          • Oral Mirtazapine (15 mg daily) may also be used as a first line agent but its use is limited due to risk of aggravating akathisia with higher doses.
          • Vitamin B6 is also used but no randomized trials are available to determine their efficacy.
        • Long term treatment involves dose reductions or switching to an antipsychotic with lower risk (Second generation antipsychotics).
      • Pseudoparkinsonism (Drug-Induced Parkinsonism)
        • Parkinson’s like symptoms occurring with First generation antipsychotics
          • Cogwheel rigidity
          • Resting tremors
          • Stiff gait
        • Occurs within 1 week of treatment induction.
        • 30-50% patients with drug induced parkinsonism show asymmetric parkinsonism.
        • May persist or even progress after the offending agent is stopped (in 10-50% of patients).
        • More commonly occur in females.
        • Diagnosis
          • Following criteria should be met:
            • Presence of parkinsonism
            • No history of parkinsonism prior to the use of offending agent.
            • Onset of symptoms during the use of offending agent.
          • Single-photon-emission computed tomography (SPECT)
          • Positron-emission tomography (PET)
        • Acute treatment:
          • Anticholinergic (e.g, Benztropine).
          • Dopamine agonists (e.g, Amantadine).
        • Long term treatment includes dose reductions or switching to drugs with a lower risk of EPS (e.g, Second Generation Antipsychotics).
      • Tardive Dyskinesia (TD)
        • Involuntary movements caused by chronic use of antipsychotic drugs.
        • More commonly involves tongue, mouth, face, limbs and respiratory muscles.
          • Lip smacking
          • Repetitive chewing
          • Choreic movements
        • The Abnormal Involuntary Movement Scale (AIMS) is used to scale the abnormal movements in TD.
        • Occurs late approximately months to years after induction of treatment.
        • Risk Factors
          • Elderly
          • Females
          • Diabetics
          • History of any mental illness
        • Treatment involves:
          • Tetrabenazine (25-150 mg daily)
          • Valbenazine (Ingrezza)
          • Deutetrabenazine (Austedo)
          • Reserpine (1-8 mg daily)
          • Clonazepam (1-4 mg daily)
          • Off label medications include Gingko Biloba, Melatonin, Vitamin B6 and Vitamin E.
        • Long term treatment involves discontinuation of the causative agent and switching to second generation antipsychotics.
        • Reducing the dosage of causative agent may initially result in worsened condition!

Long QT Syndrome (LQTS)

    • Prolonged QT interval occurs commonly with ALL antipsychotics.
    • IV Haloperidol and Thioridazine are the most common agents among first generation antipsychotics.
    • Ziprasidone and Iloperidone more commonly cause prolonged QT interval among second generation antipsychotics.
    • Treatment is indicated in QTc prolongation more than 500 ms with:
      • IV Magnesium 2-4 gm over 10 minutes.
      • Dose reductions or change of medication may be considered to avoid further episodes.

Orthostatic Hypotension

    • Orthostatic Hypotension is one of the rare side effects of antipsychotic medications.
    • It occurs due to inhibition of Alpha Adrenergic receptors.
    • The risk of orthostatic hypotension associated with antipsychotic therapy is increased in patients with disorders of the autonomic nervous system, fluid imbalance and those taking drug therapy that affects haemodynamic system.
    • Occurs most commonly with low potency first generation antipsychotics (e.g, Chlorpromazine).
    • Also commonly occurs with Olanzapine.
    • Commonly occurs during treatment initiation and drug adjustments.
    • Treatment:
      • Non pharmacological treatments (e.g, drug substitution)
      • Fludrocortisone is the first line when nonpharmacological treatment fails and there is a necessary indication to continue use of antipsychotic treatment.
      • Desmopressin and Midodrine are second line agents (preferably avoided due to side effect profiles).

Neuroleptic Malignant Syndrome (NMS)

    • Although uncommon, neuroleptic malignant syndrome is a life threatening condition with 10-12% mortality rates.
    • Although any antipsychotic can cause this condition, but following are the drugs most commonly associated with NMS:
      • High potency first generation antipsychotics (e.g, Haloperidol)
      • Carbamazepine
      • Lithium
      • Venlafaxine
      • Promethazine
      • Metoclopramide
    • Genetic predisposition may play a role.
    • Duration or therapeutic doses of drugs have not been clearly linked to the incidence of NMS.
    • Pathophysiology
      • The underlying mechanism is not fully understood but involvement of different neurotransmitter pathways are involved. Following is the brief description:
        • Central dopamine (D2) receptor blockade in nigrostriatal pathway.
        • Increased sympathetic tone resulting in autonomic dysregulation.
        • Increased release of calcium from muscle cells resulting in increased contractility and muscle tone.
    • Clinical features
      • Onset occurs usually within 2 weeks of initiation of therapy.
      • Muscle rigidity
      • Hyperthermia
      • Confusion
      • Delirium
      • Stupor
      • Autonomic instability ( tachycardia, dysrhythmias, unstable blood pressures etc)
    • Labs
      • Leukocytosis
      • Increased creatinine
      • Myoglobinuria
      • Metabolic acidosis
      • Increased transaminases
      • Low serum iron
      • Hyperkalemia
      • Hypocalcemia
      • hyponatremia/hypernatremia
    • Treatment
      • Supportive measures ( ICU protocols)
      • Discontinuation of the causative agent
      • Dantrolene - ryanodine receptor antagonist that prevents the release of calcium from the sarcoplasmic reticulum of striated muscle cells, reducing muscle rigidity and hyperthermia.
      • Bromocriptine, Apomorphine can be used as second line agents.
      • Benzodiazepines for psychomotor agitation.

Further Reading

  • Fahn S, Jankovic J, Hallett M. The tardive syndromes: Phenomenology, concepts on pathophysiology and treatment, and other neuroleptic-induced syndromes. In: Fahn S, Jankovic J, Hallett M, editors. Philadelphia, PA: Elsevier Sanders; 2011. pp. p 415–446. Principles and practice of movement disorders, 2nd ed
  • Expert Rev Clin Pharmacol. 2008;1(6):791-802
  • Gossman W, Sangani A, Saadabadi A. Neuroleptic Medications. [Updated 2019 Jul 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-.
  • Berman BD. Neuroleptic malignant syndrome: a review for neurohospitalists. Neurohospitalist. 2011;1(1):41–7.

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