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Medication management of depression Stephen Bazire, Chief Pharmacist Norfolk and Waveney Mental Health Partnership NHS Trust.

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Presentation on theme: "Medication management of depression Stephen Bazire, Chief Pharmacist Norfolk and Waveney Mental Health Partnership NHS Trust."— Presentation transcript:

1 Medication management of depression Stephen Bazire, Chief Pharmacist Norfolk and Waveney Mental Health Partnership NHS Trust

2 Suicide Suicide is a fatal outcome of psychiatric illness Suicide practically does not occur without the presence of mental illness, most commonly depression, then alcoholism. Depressed individuals who have committed suicide are seldom treated with antidepressants Does increased antidepressant use reduces suicide? 14 studies say yes, 2 say no Effect may be even greater in bipolar disorder where the lithium effect is greater Göran Isaacson, Acta Psychiatr Scand 2006;114:149-50

3 Effects of treating depression Sweden: Two year educational programme (GPs on Gotland) Increased antidepressant use Reduced referral, sick leave and in-patient days for depression Significantly reduced suicide (Rutz et al, Acta Psych Scand 1989;80:151-4) Sweden: Annual on-going educational programme (GPs in Jämtland county) Antidepressant use increased from 25% below national average to the same level Suicide decreased to the national average (Henriksson and Isacsson, Acta Psychiatr Scand 2006;114:159-67) Denmark: Suicide rate (1995-1999) has dropped in all groups More markedly in people prescribed SSRIs or older antidepressants (n=438,625) Compared to those not treated with antidepressants (n=1,199,057) (4yrs, Søndergård et al, Acta Psychiatr Scand 2006;114:168-76)

4 10% increase in SSRIs reduced suicide rate by 1.4% 10% increase in 2nd gen n reduced suicide rate by 1.2%

5 Counselling vs antidepressants Mild to moderate depression, community Antidepressants vs generic counselling 4 treatment groups: Randomised to antidepressants or counselling (n=103) Patient preference to antidepressants or counselling (n=103) No outcomes difference between groups (!) Beck scores, Psychiatrists assessment Patients choosing counselling did slightly better than those randomised to it Both seem equally effective in mild-to-moderate depression (n=323, RCT, 8/52+12/12, Chilvers et al, BMJ 2001, 322, 722-75)

6 Drug-induced depression Over 150 drugs reported to cause depression e.g: Alcohol Benzodiazepines e.g diazepam, clonazepam, temazepam, lorazepam Antipsychotics Anticonvulsants e.g. carbamazepine, lamotrigine, levetiracetam, pregabalin, topiramate Anti-parkinsonian drugs Anticholinergics H2 blockers Interferons (controversial) NSAIDs eg ibuprofen Cardiovascular drugs e.g. beta-blockers, calcium channel-blockers Antibiotics (rare) Baclofen (rare) Steroids (e.g. dexamethasone) Caffeine/caffeine withdrawal Oral contraceptives Simvastatin Dantrolene Tizanidine Check doses, starting, stopping, previous history Ref Psychotropic Drug Directory 2007, SPCs, BNF

7 Antidepressants available in UK SSRIs: Citalopram (Cipramil), escitalopram (Cipralex), fluoxetine (Prozac), fluvoxamine (Faverin), paroxetine (Seroxat), sertraline (Lustral) Mirtazapine (Zispin) Venlafaxine (Efexor) Tricyclics: amitriptyline, clomipramine (Anafranil), dothiepin/dosulepin, doxepin (Sinequan), lofepramine (Gamanil), imipramine, maprotiline, nortriptyline, trimipramine (Surmontil) Duloxetine (Cymbalta) Trazodone (Molipaxin) Reboxetine (Edronax) Moclobemide (Manerix) MAOIs: Phenelzine, isocarboxazid, tranylcypromine Mianserin, tryptophan, flupenthixol (Fluanxol) Agomelatine (2008), St. Johns wort

8 Comparative side effects of antidepressants

9 Modes of action and receptors SSRIs- 5-HT reuptake inhibition Mirtazapine - increased 5-HT and NE availability, 5-HT2 and 5- HT3 antagonism Venlafaxine and duloxetine - 5-HT and NA reuptake inhibition (venlafaxine variable, duloxetine similar) Trazodone- 5-HT reuptake inhibition and some receptor antagonism Tricyclics - 5-HT and NE reuptake inhibition Reboxetine - noradrenaline reuptake inhibition Flupenthixol - Autoreceptor inhibition Moclobemide- Reversible MAO-A inhibition MAOIs - Inhibition of MAO-A and MAO-B enzymes Agomelatine- 5HT 2C/2B antagonist and melatonin M 1/2 agonist Relevance: as long as it works, side effects

10 Selected antidepressant side effects Anticholinergic – dry mouth, blurred vision, constipation Cardiac – prolonged QTc, postural hypotension, tachycardia, Nausea – initial, start with lower doses Sedation - mostly histaminergic effect Overdose toxicity – cardiac Pro-convulsant – bupropion at >300mg/d Sexual dysfunction – lower libido, ED, anorgasmia Anxiety (short-term esp. with SSRIs), appetite changes, hyponatremia (except mirtazapine), diarrhoea, headache, sweating (esp. at night) Many can be minimised by starting at lower doses In Mirtazepine, if a patient is too drowsy on the 15mg dose, push UP to the 30mg dose. I know this sounds illogical, but the 15mg dose is more drowsier than the 30mg (there is a pharmakinetic reason behind this)

11 Usual therapeutic doses for depression SSRIs: Citalopram (Cipramil) 20-40mg Escitalopram (Cipralex) 10mg Fluoxetine (Prozac) 20mg fluvoxamine (Faverin) 150-300mg? Paroxetine (Seroxat) 20-30mg Sertraline (Lustral) 50-100mg Tricyclics: amitriptyline, clomipramine (Anafranil), dothiepin/dosulepin, doxepin (Sinequan), imipramine, nortriptyline, trimipramine (Surmontil) – 125-150mg/d Lofepramine (Gamanil) 140-210mg Newer: Mirtazapine (Zispin) 30-45mg Venlafaxine (Efexor) 75-225mg Duloxetine (Cymbalta) 60-120mg Trazodone (Molipaxin) 150mg? Reboxetine (Edronax) 8-12mg Moclobemide (Manerix) 300mg MAOIs: Phenelzine 45mg? Isocarboxazid 30mg? Tranylcypromine 30mg? Mianserin, tryptophan, flupenthixol (Fluanxol), agomelatine (soon) St. Johns wort

12 Onset of action of antidepressants Antidepressants take 4 weeks to work Wrong! 23% of all drug-placebo differences occur within the first week and 57% were apparent by week 2 (s=47, n=8500, d/b, p/c, Pasternak and Zimmerman, J Clin Psych 2005, 66, 148-58) Time to substantial remission may take 4 weeks in clinical trials and that is why doctors usually say it may take up to 4 weeks to see whether it works or not (which is the right thing to say) In 90% cases substantial improvement occurs within the first 2 weeks but that the benefit continues to build over several weeks. (review by Mitchell, B J Psych 2006, 188, 105-6)

13 Markers of antidepressant response If no improvement (even minimal) after 4 weeks of a therapeutic dose, should switch to another one With minimal improvement, continue until week 6 but there is only benefit in continuing in about 10% pts (n=593, Quitkin et al, Arch Gen Psychiatry 1996, 53, 785-92 If there is no response by 8 weeks then the trial should be declared a failure (n=840, 12/52, open, Quitkin et al, Am J Psych 2003, 160, 734-40) Only 58% people take antidepressants for more than 28 days (n=829, Offson et al, Am J Psych 2006, 163, 101-8).

14 Duration of antidepressant therapy summary 40% of people may relapse after an index depressive episode within 2 years, and 60% within 5 years First episode: Six months after recovery at same dose minimises risk of relapse (n=839, RCT, one-year, Reimherr et al, Am J Psych 1998, 155, 1247-53 Second episode: 1-2 years Third or subsequent episode: 3-5 years or longer (Frank and Kupfer, Arch Gen Psych 1990 and 1992)

15 Depression relapse prevention Full-dose vs. half-dose tricyclics

16 Relapse prevention

17 Discontinuing or switching antidepressants Why discontinue or switch antidepressants? Lack of efficacy Adverse effects Patient discontinues of own accord End of maintenance phase

18 What you can do if there is a lack of response 1. Increase the dose 2. Switch antidepressants 3. Augment with: another antidepressant mood stabiliser anxiolytic another drug e.g. pindolol, thyroxine etc

19 1. Increasing the dose - types of dose-efficacy relationship

20 Summary of dose-response curves

21 Fluoxetine fixed-dose study Altamura et al, B J Psych 1988, 153(Suppl 3), 109-112

22 Fluoxetine fixed-dose study Altamura et al, B J Psych 1988, 153(Suppl 3), 109-112

23 Venlafaxine dose-response Rudolph et al, J Clin Psychiatry 1998, 59, 116-122

24 The chances of success with increasing dose: Limited: SSRIs (generally side effects limited) Mirtazapine (unknown) Possible: Tricyclics (side effects increase) MAOIs (side effects and toxicity increase) Probable: Venlafaxine (side effects increase)

25 Switching antidepressants Factors to consider: Speed at which the switch is needed Current dose of the first drug Individual drugs effects, transmitter effects, kinetics etc Individual susceptibility to (additive) side-effects Potential problems: Cholinergic rebound Antidepressant discontinuation symptoms Drug-drug interactions Discontinuation effects from first drug interpreted as side-effects of the second Serotonin Syndrome for drugs affecting serotonin

26 Serotonin syndrome Definition - a toxic state caused by an increase in brain serotonin activity. Symptoms 1. Neuromuscular Restlessness Myoclonus Tremor and rigidity Hyperreflexia 2. Others Shivering/elevated temperature Arrhythmias etc. Can be fatal due to cardiac collapse Causes Most often with combined or consecutive treatment with SSRIs, tricyclics, MAOIs, tryptophan etc Treatments Stop drugs - usually resolves in no more than 24 hours Symptomatic measures e.g. cooling, BDZs Prevention take care when combining or switching serotonergic antidepressants

27 Discontinuation phenomena Characteristics: Commence within 1-3 days of stopping or reducing doses Usually short-lived (1-2 weeks) Rapidly suppressed by re-introduction of drug Distinct from relapse or recurrence, which occur 2+ weeks after discontinuation Can occur even with missed doses

28 Discontinuation symptoms Tricyclics: Cholinergic rebound headache, restlessness, diarrhoea, nausea flu-like symptoms, cramps lethargy sleep disturbances movement disorders SNRI (venlafaxine): Fatigue, headache, restlessness, nausea abdominal distension, congested sinuses SSRI discontinuation: Dizziness, light-headedness Sleep disturbances agitation, volatility electric shocks in the head nausea, fatigue, headache flu-like symptoms Mirtazapine & reboxetine: Little or nothing reported MAOIs: Confusion, delirium, psychosis

29 Paroxetine discontinuation

30 MedEd technique

31 Depression in bipolar disorder Bipolar depression: is more resistant and longer-lasting up to 50% may still be depressed at one year (Hlastala et al, Depress Anxiety 1997, 5, 73–83) may respond to mood stabilisers e.g. lithium, valproate, carbamazepine etc is susceptible to manic switch, especially in first 12 weeks use lowest switch risk drugs, eg. SSRIs, mirtazapine Beware of inducing a mixed state in bipolar III risk of self-harm/suicide is high

32 Antidepressants in bipolar depression Antidepressant (paroxetine <40mg/d or bupropion <375mg/d) or placebo plus Mood stabiliser (lithium, valproate, carbamazepine or a licensed antimanic agent e.g. olanzapine, risperidone, aripiprazole, quetiapine, ziprasidone) Outcome aim was 8/52 euthymia: Mood stabiliser and antidepressant response 23.5% Mood stabiliser and placebo response 27.3% Longer-term adjunctive antidepressants have no therapeutic advantage but at least the antidepressant did not increase the risk of relapse or switch to mania nor have greater ADRs (n=366, RCT, d/b, p/c, 26/52, STEP-BD, Sachs et al, N Engl J Med 2007;356:1-12)

33 Quetiapine in bipolar depression BOLDER 1 n=542, MD episode in Bipolar I or II Response 600mg/d = 58.2% 300mg/d = 57.6% placebo = 36% Remission 52.9% vs 28.4% Treatment emergent mania 3- 4% for both groups (n=542, RCT, d/b, p/c, 8/52, Calabrese et al, Am J Psych 2005, 162, 1351-60) BOLDER 2 Quetiapine 300mg and 600mg/d monotherapy equally effective in bipolar I and II depression 53% response in BD (n=542, RCT, 8/52, p/c, Hirschfeld et al, J Clin Psychiatry 2006;67:355-62).

34 Lamotrigine Lamotrigine 50–200mg/d monotherapy significantly more effective than placebo in bipolar I depression n=195, RCT, Calabrese et al, J Clin Psychiatry 1999, 60, 79–88 Survival rates favoured lamotrigine, with 41% stable without relapse at 6/12 (cf 26% placebo) Well-tolerated, may thus be useful in some rapid-cyclers n=324, open + n=182 d/b maintenance phase, Calabrese et al, J Clin Psych 2000, 61, 841-50 Two unpublished, negative studies Unlicensed in UK, and never will be NICE mentioned for relapse prevention of bipolar depression

35 Conclusion Depression is a chronic condition and antidepressants: are effective in acute depression prevent relapse are not addictive nor dependence prone help correct a chemical imbalance have no major documented long-term harmful effects appear to be widely used sub-optimally Resistant depression might be undiagnosed bipolar Education about antidepressant use should be integral with all prescribing, as it improves attitudes and hence concordance

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