This document discusses the treatment of depression with antidepressant medications. It covers the stages of acute, continuation, and maintenance treatment. It describes the mechanisms of action and side effect profiles of different classes of antidepressants including tricyclic antidepressants, selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and serotonin-norepinephrine reuptake inhibitors. Factors to consider in choosing an antidepressant and ensuring patient adherence are also discussed.

1. Dr Eleni Palazidou MD, PhD, MRCP, FRCPSYCH

2. 1. Fawcett J, Barkin RL. J Clin Psychiatry . 1997; 58(Suppl 6): 32 – 39. 2. O'Reardon JP, Amsterdam JD. Psychiatr Ann 1998; 28: 633 – 640. Approximately 2/3 of patients treated for depression will fail to achieve remission (HAM-D ≤ 7) 2

3. 1. Paykel ES, et al. Psychol Med 1995; 25: 1171 – 1180. Patients were interviewed at 3-monthly intervals according to the Clinical Interview for Depression and HAM-D 17 Rating Scale Depressed patients with unresolved symptoms are 3 times more likely to relapse 1

4. Kupfer DJ. J Clin Psychiatry 1991; 52 (5, Suppl): 28–34.

5. 1. Acute Treatment First 6-12 weeks of treatment - aims at remission (control of symptoms). Inadequate response is associated with poor prognosis. 2. Continuation Treatment 6 months after full symptom control - to maintain remission status and relapse prevention. 3. Maintenance Treatment Aims at prevention of recurrence of a further episode of depression. Indicated when higher risk of these recurrence. “ maintenance dose”

6. Treatment aims Complete symptom resolution Return to premorbid functioning (psychosocial, occupational) The maintenance of normality The prevention of recurrence

7. Limbic System Prefrontal Cortex Locus Coeruleus (NA source) Raphe Nuclei (5-HT source) Amygdala Hippocampus Cooper JR, et al. The Biochemical Basis of Neuropharmacology . 8th ed. New York: Oxford University Press; 2003. Descending 5-HT pathways Descending NA pathways

8. Normal situation Depression

9. Monoamine oxidase inhibitors -non-selective, non-reversible (MAOIs) -selective, reversible (RIMAs) Monoamine re-uptake inhibitors -non-selective NA & 5-HT (TCAs) -selective NA & 5-HT (SNRIs) -selective 5-HT (SSRIs) -selective NA (NARIs) Receptor selective antagonists -alpha2 receptor antagonists – mianserin, mirtazapine -5-HT2 receptor antagonists - trazodone

10. ACUTE MECHANISM OF ACTION UNDESIRABLE PHARMACOLOGICAL ACTIONS TCAs Anticholinergic; antihistaminic; alpha1 adrenoceptor blockade; direct membrane stabilisation SSRIs Citalopram(Cipromil), Fluoxetine (Prozac), Fluvoxamine(Faverin), Paroxetine(Seroxat), Sertraline (Lustral) 5-HT re uptake inhibition MAOIs Phenelzine(Nardil), Isocarboxazid(Marplan) Tranylcypromine(Parnate) Inhibition of MAO-A and MAO-B isoenzymes Interaction with tyramine and sympathomimetic drugs; Irreversible and non-selective inhibition of MAO isoenzymes RIMAs Moclobemide(Manerix) Reversible Inhibition of MAO-A SNRIs Venlafaxine(Efexor) Duloxetine(Cymbalta) 5-HT and NA re uptake inhibition Reboxetine(Edronax) NA re uptake inhibition Mirtazapine(Zispin) Alpha2 adrenoceptor blockade 5-HT2 receptor blockade

11. Normal situation Depression

12. Side effects ↑ Weight, sexual dysfunction, dry mouth, headache Safety in overdose Lethal (hypertensive crisis, stroke,MI) Sympathomimetics ¢ Tyramine foodstuffs ¢ Carbamazepine ¢ Hypertensive crisis β -blockers ↑ hypotension,bradycardia Oral hypoglycaemics ↑ hypoglycaemic effect SSRIs ¢ Nefazodone Serotonin Syndrome Bupropion ¢ Hypertensive crisis, seizures Clomipramine ¢

13. SIDE EFFECT PROFILE OF TRICYCLIC ANTIDEPRESSANTS Anticholinergic Dry mouth, Blurred vision Urinary hesitancy (urinary retention) Constipation Memory impairment Aggravation of narrow angle glaucoma Antihistaminic Sedation Weight gain Alpha1 adrenoceptor antagonism Orthostatic hypotension Cardiac effects Cardiovascular effects Sinus tachycardia Arrhythmias Conduction delay Sudden death Other side effects Sexual dysfunction Impaired cognitive and psychomotor skills Convulsions

14. SIDE EFFECT PROFILE OF SSRIs Nausea/vomiting* Abdominal pain Dry mouth Constipation/diarrhoea Headache* Asthenia Dizziness Insomnia/somnolence Sweating* Anorexia Weight loss Nervousness/agitation Tremor Convulsions Dystonic reactions Sexual dysfunction* (reduced libido, anorgasmia)

15. Serotonin Syndrome – Suggested Diagnostic Criteria Coincident with the addition of or increase in a known serotonergic agent to an established medication regimen, at least three of the following clinical features are present: mental status changes (confusion, hypomania) agitation myoclonus hyperreflexia diaphoresis shivering tremor diarrhoea incoordination fever Other aetiologies (e.g. infectious, metabolic, substance abuse or withdrawal) have been ruled out. A neuroleptic had not been started or increased in dosage prior to the onset of the signs and symptoms listed above.

16. DISCONTINUATION SYNDROME Dizziness * Electric shock sensations * Anxiety/agitation ٭ Insomnia Flu-like symptoms Diarrhoea/abdominal spasms Paraesthesia * Mood swings Nausea Low mood

17. Pharmacokinetic – cytochrome p450 Pharmacodynamic – MAOIs + SSRIs (serotonin syndrome)

18. CYP2 D6 polymorphism- autosomal recessive trait (slow or ultra-rapid metabolisers)

19. Tricyclic antidepressants (Lofepramine) Venlafaxine MAOIs

20. Antidepressant drugs: - Induction of mania/mixed states - Cycle acceleration (rapid cycling) - Uncertainty about duration of Rx

21. Choice of medication Severity of illness Clinical presentation Suicidal risk Previous response to treatment The likely tolerability of potential side effects The likely benefit of potential side effects such as sedation The likely drawbacks of potential side effects such as sedation (i.e. working with machinery, driving etc) Pregnancy or breastfeeding Concomitant treatment of physical illness or other psychiatric disorders with the potential for pharmacokinetic/pharmacodynamic interactions. The presence of relevant physical (for example cardiovascular) disease

22. Therapeutic alliance Adequate information about the nature of their illness and the need for treatment. A positive message about the treatability Explain that antidepressants are not addictive, do not alter one’s personality nor affect their intelligence . It may take about 2 -4 weeks before s/he their symptoms start showing significant improvement T hey may experience some side effects A ntidepressant could be changed if they are unable to tolerate the original drug prescribed. Regular reviews of the patient’s mood state and suicidal risk offers further reassurance and support, helps ensure compliance and allows prompt intervention in the case of any serious worsening of the condition.

23. 1960s-70s First generation – “classical” Phenothiazines - chlorpromazine Butyrophenones - haloperidol Thioxanthines - flupenthixol From 1980s Second generation – “atypicals” Clozapine, olanzapine, quetiapine, Sulpiride, amisulpride Risperidone, paliperidone Aripiprazole

25. Extrapyramidal Parkinsonism Dystonia Akathisia Tardive dyskinesia Hyperprolactinaemia Amenorrhoea Low fertility Sexual dysfunction Cardiovascular – QT interval Haematological Weight gain Lower seizure threshold Drug interactions

26. Effective – when 60% D2 receptor occupancy EPS - when 80% D2 receptor occupancy (shown on PET scanning ) EPS Prevalence Rx parkinsonism 30% anticholinergic drugs amantadine dystonia 21%(young males) anticholinergic drugs akathisia 25% - 75% propranolol tardive dyskinesia 10-20% (>1year Rx) * neuroleptic malignant syndrome Males>females bromocriptine dantrolene diazepam

27. Schizophrenia Bipolar disorder Obesity 45-55% 26% Smoking 50-80% 55% Diabetes mellitus 10-14% 10% Hypertension >18% 15%

28. Reasons for intolerance (total 15%) weight gain/metabolic – 4% EPS – 4% Sedation – 2% Other – 5% Efficacy on +ve and -ve symptoms no difference between 1 st and 2 nd generation

29. Electrolyte imbalance ( ↓ K, ↓ Mg) Underlying cardiac abnormalities Hypothyroidism Familial QT prolongation Σ Drugs known to prolong QT

30. Higher risk of QTc prolongation and Torsades de Pointes – iv administration or high doses Recent recommendation an ECG to be performed prior to Rx

31. Great variation in pharmacological profile! In general they have decreased likelihood of extrapyramidal effects or hyperprolactinaemia BUT Weight gain Diabetes Metabolic syndrome

32. First generation Second generation Weight gain Hyperglycaemia, diabetes Insulin resistance Cardiovascular dis Dyslipidaemia Less EPS Less QT prolongation Less hyperprolactinaemia Neurological side effects EPS Tardive dyskinesia Hyperprolactinaemia

34. Antipsychotic drugs Schizophrenia, other psychoses and any psychotic symptoms sometimes useful as sedatives Antidepressants Depression Anxiety Obsessive compulsive disorder

35. Drug treatment needs to be tailored to the individual The aim is to achieve full symptom control Return to pre morbid functioning Minimize side effects, ensure safety Monitor progress over time as mental illnesses are long term relapsing conditions Always check suicide risk