Anti-depressants in Palliative Medicine

1. Anti-depressants in Palliative Medicine Rebecca Owen 24.10.12

2. Depression • Common in Palliative Care • 15% meet criteria for major depressive disorder and many more experience depressive symptoms1 • Associated with: • Increased pain/fatigue1 • Reduced treatment adherence1 • Poorer prognosis1 • Higher mortality in range of physical illnesses1

3. Pathophysiology • Limbic and prefrontal cortex circuits regulate mood, attention, energy, appetite & sleep • Adapt structurally and functionally to external stimuli (neuroplasticity) • Impaired in depression • Complex interaction between neurotransmitter availability and receptor regulation & sensitivity underlying affective symptoms.

4. Involved Neurotransmitters • Serotonin (5-HT) • Norepinephrine(NE) • Dopamine (DA) • Glutamate • Brain-derived neurotrophic factor (BDNF).

5. Pharmacology 2 • Help restore impairment • Monoamines trigger release of nerve growth factors such as BDNF • Analgesic effect due to enhancement of mono-amine transmission by descending pain modulation pathway • Can induce analgesia (NE and 5HT activity) and hyperalgesia (5HT activity)

6. Beneficial and undesirable effects of antidepressants can vary because of: • Mechanisms of action • Monoamines affected • Effect on other receptors • Pharmacokinetic profiles

7. Predominant mechanism of Action2

8. Box 4e pcf 4

9. Transporter and receptor affinities for selected antidepressants2

10. Pharmacokinetic details for selected antidepressants2

11. Suicide Risk and Antidepressants • 1 in 1000 patients attempt suicide 6/12 after starting an anti-depressant • If pt <25 yrs – can cause suicidal ideation and self harm (NNH 143) • SSRIs > TCAs • If pt >25 yrs – smaller increase in self harm (NNH 700), but no increase in suicidal ideation • No difference between SSRIs and TCAs

12. Epilepsy and Antidepressants • Cause dose-dependent reduction in seizure threshold • Lowest for SSRIs • Citalopramfavoured (less interactions with other drugs) • Mirtazepine & Venlafaxine – less experience & data • Higher risk with TCAs • Highest with Clomipramine, Bupropion & Maprotiline • Can also cause seizures through hyponatraemia or alterations of anti-epileptic drug levels

13. Parkinson’s Disease and Antidepressants • SSRIs – can worsen extrapyramidal symptoms • serotonin reduces nigrostriatal dopamine release via inhibitory 5HT2 receptors • Small risk (only few RCTs report any worsening) • TCAs – Can worsen autonomic dysfunction (α blockade) & cognitive impairment (AChm blockade) • SSRIs preferred to TCAs

14. Serotonin Syndrome • Results from ingestion of drugs which increase brain serotonin levels to cause: • Autonomic hyperactivity • Neuromuscular activity • Altered mental status • Onset rapid & progressive • Usually if 2ndserotoninergic drug reaches effective levels • Essential features: • Clonus, agitation, sweating, tremor, hyperreflexia

15. Drugs with serotoninergic potency 1 • Antidepressants – MAOIs • (all types) • Antidepressants – SSRIs • (all types) • Antidepressants – SNRIs • Clomipramine, Imipramine, Duloxetine, Milnacipran, Venlafaxine • Psychostimulants (serotonin releasers) • Dexamfetamine, MDMA (Ecstasy), (NOT METHYLPHENIDATE)

16. Drugs with serotoninergic potency 2 • H1 antihistamines (serotonin re-uptake inhibitors • Chlorphenamine, Brompheniramine • Opioids (serotonin re-uptake inhibitors) • Fentanils, Methadone, Pethadine, Tramadol • MAOIs • Furazolidone, Linezolid, Methylene blue, Procarbazine, Selegiline • SNRIs • Sibutramine

17. Treatment of Serotonin Syndrome • In severe cases, seek urgent advice from critical care specialist • Rigidity, haemodynamic instability, temp > 38.5°C • Discontinue causal meds • Supportive care (IV fluids, O2) • Symptomatice measures • BZD; agitation, myoclonus, seizures • 5HT2A antagonist; e.g. Chlorpromazine, Olanzapine, Cyproheptadine

18. Undesirable effects of SSRIs • SSRIs + SNRIs decrease serotonin uptake from blood by platelets • Therefore reduces overall levels in platelets • Adversely affects platelet aggregation • SSRIs triple the risk of GI bleeding • If high risk patient – to consider use of NRI e.g. nortriptylline, mirtazepine

19. Typical symptoms suggestive of depression

20. Treatment of Mild Depression

21. Treatment of Moderate Depression

22. Treatment of Severe Depression

23. Treatment resistant depression

24. Short Prognosis

25. Before starting antidepressant treatment

26. Choice of Antidepressant

27. Mirtazepine – Benefits • Increase appetite • Reduce nausea • Sedative effect may be beneficial for some patients • May have early onset of action, therefore a good choice for patients with a short prognosis • Available as orodispersible tablet • Suitable in heart failure and diabetes

28. Mirtazepine Possible Side Effects Cautions possible increased serotonergic effects when given with tramadol or venlafaxine enhances anticoagulant effect of warfarin • sedation • dizziness • constipation • hypertension • weight gain • oedema • orthostatic hypotension • dry mouth • fatigue, tremor • dizziness • confusion, anxiety • arthralgia, myalgia

29. Sertraline Benefits Possible Side Effects Nausea, vomiting, drowsiness, dizziness, dry mouth, anorexia,dyspepsia, diarrhoea, insomnia, sweating, sexual dysfunction, agitation, hyponatraemia, pancreatitis, hepatitis, jaundice, liver failure, tachycardia, amnesia, paraesthesia, aggression, urinary incontinence, menstrual irregularities • Beneficial for renal impairment • First choice for recent cardiac event • Cautions • Risk of ventricular arrhythmias if taken with droperidol • Increased risk of bleeding when given with aspirin

30. Citalopram Benefits Possible Side Effects Nausea, vomiting, anorexia, dyspepsia, diarrhoea, dry mouth,dizziness, insomnia, sweating, sexual dysfunction, agitation, hyponatraemia, palpitation, tachycardia, postural hypotension, confusion, impaired concentration, amnesia, migraine, paraesthesia, taste disturbance, increased salivation, rhinitis, tinnitus, polyuria, micturition disorders, euphoria, abnormal dreams • Beneficial for agitated depression/anxiety, nausea • Relatively safe for patients at risk of seizures • Available as oral suspension • Cautions • Increased risk of bleeding when given with aspirin • Possibly greater risk in overdose than other SSRIs

31. Amitriptylline Benefits Possible Side Effects Dry mouth, constipation, hypotension, tachycardia, urinaryretention, confusion, dizziness, sleep disturbance, drowsiness, arrhythmia, abdominal pain, stomatitis, palpitation, oedema, restlessness, fatigue, mydraiasis, increased intra-ocular pressure, sexual dysfunction, nausea, sweating • May be beneficial for patients with insomnia or neuropathic pain • If a patient is already on a low dose for neuropathic pain, it may be beneficial to increase this dose, rather than introduce another antidepressant • May have an earlier onset of action than SSRIs • There is evidence that TCAs are equally, if not more effective than SSRIs • Cautions • Greater toxicity in overdose than SSRIs

32. Physical disease contraindications of antidepressants 1

33. Physical disease contraindications of antidepressants 2

34. Physical disease contraindications of antidepressants 3

35. Stopping Antidepressants • Withdrawal syndrome can occur after abrupt cessation following >8 weeks of regular administration of antidepressant • More common with drugs with shorter half lives • Most common with Paroxetine • Least common with fluoxetine • Start within few days of stopping Rx • Resolve within 24 hrs of restarting Rx • Should progressively reduce over 4/52

36. In Summary • High prevalence of depression in palliative care • Detecting depression is particularly challenging • somatic symptoms, such as fatigue and insomnia, may be due to depression, advanced disease or medical treatment • difficult to distinguish from normal fear and sadness which often accompany terminal illness • Psychological therapy and antidepressant drugs are mainstay of treatment

37. References • The Management of Depression in Palliative Care. European Clinical Guidelines 2010. • Palliative Care Formulary 4th Edition; Twycross & Wilcock 2011.