6.8: Central Nervous System & Mental Health Therapeutics
Key Takeaways
- SSRIs are first-line for depression/anxiety; monitor young adults (<25 years) closely for emergent suicidal ideation in the first 2-4 weeks.
- Lithium has a narrow therapeutic range (0.6-0.8 mmol/L maintenance); thiazide diuretics, ACE inhibitors, and NSAIDs significantly increase serum levels.
- Atypical antipsychotics have lower EPSE risks than typicals but cause metabolic syndrome; clozapine requires mandatory FBC monitoring for agranulocytosis.
- Phenytoin displays non-linear kinetics with a target range of 10-20 mg/L (40-80 umol/L); sodium valproate is contraindicated in childbearing potential unless strict criteria met.
6.8 Central Nervous System & Mental Health Therapeutics
Mental health and neurological conditions represent a significant portion of Australian clinical practice. Pharmacists must understand treatment algorithms, safety monitoring, side effects, and drug-drug interactions for depression, anxiety, bipolar disorder, schizophrenia, epilepsy, and Parkinson's disease.
1. Depression and Anxiety Disorders
Depression Treatment Algorithm
First-line pharmacological management for major depressive disorder (MDD) consists of Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., sertraline, escitalopram, fluoxetine) due to their safety profile in overdose and tolerability.
- Initiation: Start at a low dose (e.g., sertraline 50 mg daily). Monitor closely for the first 2-4 weeks, especially in patients under 25 years old, due to a transient increase in suicidal ideation and agitation.
- Evaluation: Efficacy is assessed after 4-6 weeks of therapeutic dosing. If there is no response, verify compliance and consider switching to a different SSRI or a Serotonin-Noradrenaline Reuptake Inhibitor (SNRI) (e.g., venlafaxine, duloxetine).
- Duration: Treatment should continue for at least 6-12 months after remission of a first episode, and longer (2+ years) for recurrent episodes.
Key SSRI/SNRI Safety Concerns
- Serotonin Syndrome: Characterized by autonomic instability (hypertension, tachycardia, hyperthermia), neuromuscular changes (tremor, hyperreflexia, clonus), and altered mental state (agitation, confusion). Requires cessation of serotonergic agents and supportive care.
- QT Prolongation: Citalopram and escitalopram have dose-dependent risks. Citalopram is capped at 40 mg daily (20 mg in patients > 65 years or with hepatic impairment). Escitalopram is capped at 20 mg daily (10 mg in elderly).
- Antidepressant Discontinuation Syndrome: Caused by abrupt withdrawal. Symptoms include "brain zaps," flu-like symptoms, dizziness, and insomnia. Prevented by tapering over several weeks. Fluoxetine has a very long half-life (active metabolite up to 2 weeks) and is least likely to cause withdrawal.
- Anxiety Disorders: SSRIs and SNRIs are also first-line for Generalized Anxiety Disorder (GAD) and panic disorder. Benzodiazepines (e.g., diazepam, oxazepam) should be restricted to short-term adjunct therapy (2 to 4 weeks) during initiation of SSRIs to manage acute agitation, due to risks of tolerance, physical dependence, cognitive decline, and falls in the elderly.
2. Bipolar Disorder
Bipolar disorder management involves treating acute mania/hypomania, acute depression, and maintaining mood stability.
Mood Stabilisers
- Lithium Carbonate: The gold standard for bipolar I disorder. It has a narrow therapeutic index:
- Target Serum Levels: 0.6 to 0.8 mmol/L for maintenance; 0.8 to 1.2 mmol/L for acute mania. Levels are drawn 12 hours post-dose (trough) at steady state (approx. 5-7 days after dose adjustment).
- Toxicity: Levels > 1.5 mmol/L cause mild toxicity (coarse tremor, vomiting, diarrhoea, muscle weakness). Levels > 2.0 mmol/L lead to severe toxicity (ataxia, confusion, nystagmus, seizures, renal failure).
- Drug Interactions (The "MAD" or "CAN" interactions): Diuretics (especially thiazides, which increase lithium reabsorption), ACE inhibitors / ARBs, and NSAIDs (except paracetamol and aspirin) reduce lithium clearance and cause toxicity.
- Monitoring: Baseline and 6-monthly TSH (hypothyroidism risk), eGFR (nephrotoxicity risk), serum calcium (hyperparathyroidism risk), and ECG.
- Sodium Valproate: Used for mania.
- Safety Alert: Valproate is highly teratogenic (neural tube defects and cognitive impairment). In Australia, it must not be used in female patients of childbearing potential unless they are enrolled in a pregnancy prevention program and other treatments are ineffective/not tolerated.
- Lamotrigine: Highly effective for bipolar depression maintenance. Requires a slow dose titration (e.g., 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks) to minimize the risk of life-threatening Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN).
3. Schizophrenia
First-line treatment utilizes atypical (second-generation) antipsychotics (e.g., risperidone, olanzapine, quetiapine, aripiprazole) over typical (first-generation) agents (e.g., haloperidol) because they have a lower risk of Extrapyramidal Side Effects (EPSEs) but carry a higher risk of metabolic syndrome.
Antipsychotic Side Effect Profiles
- Metabolic Syndrome: Weight gain, dyslipidaemia, impaired glucose tolerance, and hypertension. Highest risk with olanzapine and clozapine.
- Extrapyramidal Side Effects (EPSEs):
- Acute Dystonia: Painful muscle spasms of neck/jaw. Treated with anticholinergics (IV/IM benzatropine).
- Akathisia: Subjective motor restlessness. Treated with beta-blockers (propranolol) or low-dose benzodiazepines.
- Tardive Dyskinesia (TD): Involuntary, repetitive movements of face/tongue. Can be irreversible. Managed by reducing dose or switching to clozapine.
- Neuroleptic Malignant Syndrome (NMS): Rare but life-threatening. Characterized by "lead-pipe" muscle rigidity, hyperthermia, autonomic instability, and elevated creatine kinase (CK). Requires immediate drug cessation and intensive care.
Clozapine Therapy
Reserved for treatment-resistant schizophrenia (failure of $\ge$ 2 other antipsychotics).
- Agranulocytosis Risk: Requires mandatory registration with a clozapine monitoring database (e.g., CPMS). Full blood counts (FBC) are required weekly for the first 18 weeks, then monthly thereafter. The Absolute Neutrophil Count (ANC) must remain $\ge$ 1.5 $\times$ 10^9/L.
- Other Serious Adverse Effects: Myocarditis (typically occurs in the first 4 weeks; monitor troponin and CRP), severe constipation/bowel obstruction, and hypersalivation.
4. Epilepsy
Anticonvulsant selection is based on the patient's seizure type and drug safety profiles.
Drug Selection by Seizure Type
- Focal Seizures: Carbamazepine, lamotrigine, levetiracetam.
- Generalized Seizures: Sodium valproate, levetiracetam, lamotrigine.
Key Anticonvulsants
- Levetiracetam: Well-tolerated with no significant drug-drug interactions. However, it can cause significant neuropsychiatric side effects, including irritability, aggression, and depression ("levetiracetam rage").
- Carbamazepine: Strong enzyme inducer and undergoes auto-induction (induces its own metabolism, requiring dose adjustment after 2-4 weeks). Can cause hyponatremia (SIADH) and SJS (strongly associated with the HLA-B*1502 allele in patients of Asian descent).
- Phenytoin: Exhibits non-linear (zero-order) pharmacokinetics at therapeutic doses. Small dose increases can lead to disproportionately large increases in serum concentrations. Therapeutic range: 10 to 20 mg/L (40 to 80 $\mu$mol/L). Toxicity signs include nystagmus, ataxia, and confusion. Chronic side effects include gingival hyperplasia, hirsutism, osteomalacia, and folate deficiency.
5. Parkinson's Disease
Pharmacological management aims to restore dopamine levels or stimulate dopamine receptors in the striatum.
- Levodopa + Dopa-decarboxylase Inhibitor (e.g., Carbidopa or Benserazide): Levodopa is the most effective drug for motor symptoms. It is always combined with carbidopa (e.g., Sinemet) or benserazide (e.g., Madopar) to prevent peripheral conversion of levodopa to dopamine, thereby reducing peripheral side effects (nausea, orthostatic hypotension) and ensuring adequate CNS penetration.
- Complications: Long-term use leads to motor fluctuations ("wearing-off" effect) and dyskinesias (involuntary choreiform movements).
- Dopamine Agonists (e.g., Pramipexole, Rotigotine): Direct stimulants of dopamine receptors.
- Adverse Effects: High risk of impulse control disorders (pathological gambling, hypersexuality, compulsive shopping) and sleep attacks (sudden onset of sleep).
- COMT Inhibitors (e.g., Entacapone): Prevent the breakdown of levodopa. Used as an adjunct to extend levodopa's duration of action in patients experiencing "wearing-off."
- Anticholinergics (e.g., Benzatropine): Used to treat tremor in younger patients, but must be avoided in elderly patients due to risk of cognitive impairment, confusion, and urinary retention.
A 34-year-old male with bipolar affective disorder has been stable on lithium carbonate 450 mg twice daily with a recent therapeutic serum lithium concentration of 0.7 mmol/L. He presents to his GP with mild hypertension and is to start antihypertensive therapy. Which of the following classes of antihypertensive medications is LEAST likely to interact with lithium or cause an elevation in serum lithium levels?
A 28-year-old female patient with treatment-resistant schizophrenia is about to commence clozapine therapy. According to Australian protocols, which of the following represents a mandatory baseline and ongoing monitoring requirement for this medication?
A 23-year-old female with generalized tonic-clonic seizures is currently taking sodium valproate 500 mg twice daily and has been seizure-free for over a year. She is planning a pregnancy in the near future. According to Australian guidelines, which of the following is the most appropriate management plan regarding her antiepileptic therapy?