Comprehensive Study Notes on Drug-Induced Movement Disorders and Antipsychotics

Drug-Induced Parkinsonism:

Acute dystonic Reactions

Tardive Dyskinesia

Neuroleptic Malignant Syndrome (NMS)

Serotonin Syndrome

Occurrence and Risk Factors:

• The condition is dose-dependent, and the risk increases with a longer duration of therapy (tardive).

• However, it can occur even with a low dose over a brief period

Common Causes:

• Antipsychotics: Most frequently associated with typical antipsychotics (e.g., Haloperidol) more so than atypical ones (e.g., Risperidone)

Treatment:

• Discontinue the causative drug.

• If parkinsonism persists despite discontinuationr, pharmacological intervention with Amantadine or Levodopa can be utilized.

Acute Dystonic Reactions

Characterized by:

• Abrupt onset of dystonic posturing.

• painful Cervico-cranial region, most often involving the ocular muscles and face.

• May be and varies in distribution.

• Oculogyric Crisis (Common MCQ Point):

  • Defined as a sustained deviation of the eyes (typically upward, but can be convergent, downward, or upward and lateral).

  • Associated Features: Often occurs with other dystonias such as backward/lateral flexion of the neck, widely opened mouth, tongue protrusion, and ocular pain.

• Onset:

  • Occurs within the first few days of exposure.

  • Typically appears within $2$ to $24\,hours$ after the first dose.

  • 
    $5\,days$.

• Causes:

  • Typically iatrogenic, resulting from a reaction to dopamine antagonist medications.

  • Other offending agents include Tetrabenazine, Methamphetamine, and Calcium Channel Blockers (CCBs).

• Treatment:

  • Discontinue the causative agent immediately.

  • Administer anticholinergics or antihistamines.

  • Specific medications: Benztropine mesylate (Cogentin) or Diphenhydramine (Benadryl).

• Prognosis:

  • Generally resolves spontaneously after drug withdrawal.

  • Resolution typically occurs within hours.

• Clinical Note: It is essential to differentiate between tardive dyskinesia and acute dystonic reactions.

Tardive Dyskinesia (TD)

• Definition and Onset (Common MCQ Point):

  • "Tardive" refers to a late onset.

  • Onset occurs after > 3\,months to several years of treatment, or sometimes after stopping the medication.

• Duration: May be transient (though must last > 3\,months) or persistent.

• Description and Symptoms:

  • Stereotypic, repetitive involuntary movements.

  • Areas Involved: Mainly oral, perioral, buccal, and lingual muscles.

  • Specific Actions: Chewing, smacking, or repetitive tongue protrusion (referred to as "flycatcher tongue").

  • Other Movements: Athetosis (slow, writhing), chorea, akathisia (inner restlessness), dystonia (often of the neck), tremors, and parkinsonism.

  • Respiratory Impact: Associated with irregular respiratory patterns and intermittent hyperventilation.

  • Masking and Aggravation: Symptoms may be masked by normal movements in mild cases ("blending into" activity). They are increased by anxiety, stress, or rapid alternating movements.

• Causes:

  • Usually dopamine antagonists, most commonly antipsychotics (Typical > Atypical).

  • Can also be caused by Metoclopramide (Common MCQ Point).

  • Lowest Incidence: Clozapine and Quetiapine have the lowest incidence rates.

• Treatment for Persistent Cases:

  • Switching Medications: Stop the drug or switch to agents with less $D_2$ receptor antagonism (e.g., Atypical antipsychotics like Clozapine and Quetiapine) if indicated for psychosis.

  • Pharmacotherapy:

    • Presynaptic dopamine depleters: Reserpine and Tetrabenazine (Common MCQ Point). These agents reduce dopaminergic synaptic activity without causing dopamine receptor antagonism.

    • Other options: Clonazepam, Amantadine, and Vitamin E.

  • Refractory Cases: Deep Brain Stimulation (DBS) is an option if pharmacotherapy fails.

• Important Contraindication (Common MCQ Point): Anticholinergic and antihistamine medications can worsen tardive dyskinesia.

Drugs Inducing Tardive Dyskinesia

• Typical Antipsychotics:

  1. Phenothiazines: Chlorpromazine (Thorazine), Prochlorperazine (Compazine).

  2. Thioxanthenes: Chlorprothixene, Thiothixene (Navane).

  3. Butyrophenones: Haloperidol (Haldol), Droperidol.

  4. Diphenylbutylpiperidine: Pimozide.

  5. Loxapine.

• Atypical Antipsychotics:

  • Thienobenzodiazepine: Olanzapine, Risperidone, Ziprasidone.

• Other Medications:

  • Benzamides: Metoclopramide.

  • Calcium Channel Blockers (CCBs): Flunarizine, Cinnarizine.

  • Tricyclic Antidepressants (TCAs): Amoxapine.

Neuroleptic Malignant Syndrome (NMS)

Causes:

1. dopamine antagonists (antipsychotics) or less commonly TCAs.

2. Rapid withdrawal from dopaminergic agents.

Description Mnemonic (FEVER):

• F: Fever / Hyperthermia (typically > 38^\circ\text{C}).

• E: Encephalopathy (altered mental status) & Extrapyramidal symptoms (rigidity and dystonia).

• V: Vital instability (Autonomic features: tachycardia, diaphoresis, labile blood pressure).

• E: Elevated Enzymes ($CK$)..

• R: Rigidity.

Clinical Indices: Rhabdomyolysis, Acidosis, and elevated Liver Function Tests ($LFTs$) may develop. Symptoms can occur early after the first dose or late after prolonged treatment.

Treatment:

1. Discontinue the causative agent.

2. Supportive Care: IV fluids and fever control.

3. Rigidity Management: Bromocriptine, Dantrolene, Benzodiazepines, or Levodopa.

4. Severe Cases: May respond to Electroconvulsive Therapy (ECT).

5. Agitation: Treated with Benzodiazepines.

Note:

Residual catatonia is a possible outcome

Serotonin Syndrome?

Causes: Combining agents that increase CNS serotonin levels, including: ( SSRIs, MAOIs, TCAs, Dopamine agonists, Sumatriptan, Meperidine, and Dextromethorphan )

Description:

• A dangerous, potentially life-threatening reaction to increased levels of serotonin ($5\text{-HT}$) in the CNS.

Clinical Presentation:

1. Cognitive: Altered mental status, agitation.

2. Neuromuscular: Tremor, hyperreflexia, rigidity, myoclonus (Lower Limbs > Upper Limbs, symmetrical, ocular, spontaneous or inducible).

3. Autonomic: Labile BP (hypotension/hypertension), fever, tachycardia, ataxia, mydriasis, shivering, and flushing.

4. Severe Cases: Hypertoxicity, hyperthermia, rhabdomyolysis, and renal failure.

Treatment:

• Discontinue the offending agent.

• Supportive care (ABC protocol, IV fluids for dehydration and fever).

• Muscle relaxants and Benzodiazepines (Diazepam, Lorazepam) for agitation, seizures, and rigidity.

• Serotonin-production blocking agents: Cyproheptadine.

• Medications to control heart rate and BP.

• In severe cases: Intubation, sedation, and skeletal muscle paralysis.

Differentiation from NMS (Common MCQ Point): Serotonin Syndrome is distinguished by the presence of shivering, myoclonus, hyperreflexia, and GI symptoms (Nausea, vomiting, diarrhea), which are uncommon in NMS.

Typical Antipsychotics (D_2 Antagonists)

General Profile: All have higher extrapyramidal side effects.

Classifications:

1. Phenothiazines:

   • Aliphatic: Chlorpromazine (Thorazine), Prochlorperazine (Compazine), Triflupromazine.

   • Piperidine: Thioridazine (Mellaril), Perphenazine.

   • Piprazine: Fluphenazine (Prolixin), Trifluperazine.

2. Thioxanthenes: Flupenthixol, Zuclopenthixol, Chlorprothixene, Thiothixene (Navane). Effective for positive symptoms; less so for negative symptoms of schizophrenia.

3. Butyrophenones: Haloperidol (Haldol), Droperidol. Favorable for emergency settings; high potential for dose-dependent acute extrapyramidal effects.

4. Diphenyl-butyl-piperidine: Pimozide (used in Tourette syndrome and Tics).

5. Dibenzo-xazepin: Loxapine.

6. Other: Molindone (Moban).

Side Effects: Weight gain, hypotension, reduced seizure threshold, anticholinergic effects, SIADH, jaundice, cataracts, agranulocytosis, tardive dyskinesia, NMS, and sudden death.

Specific Notes:

Thioridazine:

• Potential for retinitis pigmentosa

• Retrograde ejaculation

• QTc prolongation.

Metabolized by cytochrome $P\text{-}450\,2D6$.

Atypical Antipsychotics (5HT_2A / D_2 Antagonists)

General Profile (Common MCQ Point): Fewer extrapyramidal side effects but a higher risk of metabolic side effects.

Specific Agents:

1. Clozapine (Clozaril): Low potency. TD is nearly absent. Good for positive and negative symptoms. Warnings: High weight gain, DM, agranulocytosis, and seizures.

2. Olanzapine (Zyprexa): Medium/high potency. High risk for weight gain.

3. Quetiapine (Seroquel): Low potency. Less sexual dysfunction, no prolactin increase. Metabolized by $CYP\,3A4$.

4. Aripiprazole (Abilify): Partial agonist at $D_2$ and $5\text{-}HT_{1A}$, antagonist at $5\text{-}HT_{2A}$. Low frequency of BP/QT changes.

5. Risperidone (Risperdal): Higher $D_2$ antagonism relative to others. High potency. Causes increased prolactin and more sexual dysfunction/motor disorders.

6. Ziprasidone (Geodon): Good for cognitions/depression. No weight gain. Warning: Can lead to QT prolongation.

7. Others: Paliperidone, Iloperidone, Lurasidone, Asenapine, Amisulpiride.

Comparative Side Effects:

• Weight Gain/Diabetes: Clozapine > Olanzapine > Risperidone.

• Movement Effects (Tremor/Agitation): Risperidone > Olanzapine > Clozapine.

• Sedation: Clozapine, Olanzapine > Risperidone.

• Sexual Dysfunction/Breast Discharge: Risperidone > Olanzapine > Clozapine.