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The 7 Ds of Depression Stephen Bazire, Chief Pharmacist Norfolk and Waveney Mental Health Partnership NHS Trust.

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Presentation on theme: "The 7 Ds of Depression Stephen Bazire, Chief Pharmacist Norfolk and Waveney Mental Health Partnership NHS Trust."— Presentation transcript:

1 The 7 Ds of Depression Stephen Bazire, Chief Pharmacist Norfolk and Waveney Mental Health Partnership NHS Trust

2 Declarations of interest (last 3 years) AstraZeneca – lectures, Bipolar Conference 2005 BMS/Otsuka - Abilify consultancy, lectures Cephalon - one day at ECNP 2004 Denfleet – 2 advisory boards Janssen-Cilag - ECNP 2005, 2006; lectures; APA 2004; CINP regional 2006 Lilly – lectures, chair meetings Lundbeck - (books) Organon - Advisory Boards, lectures, (books) Sanofi-Synthelabo - lectures, thermal mug Servier – Advisory Board Wyeth – Advisory Board, lectures UK Psychiatric Pharmacy Group User groups, Norfolk Mental Health Alliance, NICE

3 Depression Diagnosis Does it matter if you treat? Drug-induced Drug Dose Duration Discontinuation

4 Depression - diagnosis A) Five of the following: Weight changes Sleep disturbance Loss of interest/pleasure Depressed mood Psychomotor agitation or retardation Recurrent thoughts of death or suicide Fatigue or loss of energy Feelings of worthlessness Poor concentration Not organic Not normal reaction to death of a loved one No delusions or hallucinations in absence of mood symptoms Not superimposed on schizophrenia

5 Is depression on the rise? Stirling County Study (Atlantic Canada) Same diagnostic criteria used Representative adult population samples 1952, n=1003 1970, n=1201 1992, n=1396 Current incidence 5% for MDD in all years Increased rate in younger women (Murphy et al, Arch Gen Psych 2000, 57, 209-15) Lundby study suggested rise in depression in 1950s has levelled off Higher incidence in women (n=3563, prospective longitudinal study, Mattisson et al, J Aff Dis 2005, 87, 151-60)

6 Underuse of antidepressants Survey 1988-1994 (USA) n=7589, aged 17-39 4.1% (312) had DSM-III major depression Only 7.4% of these were having antidepressants Telling prescriber the symptoms increased chance of having an antidepressant 10-fold Druss et al, J Clin Psych 2000, 61, 234-7

7 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

8 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)

9 The effect of antidepressants on suicide rates in USA 1985-1999 analysis: 20,000 pharmacies in USA Volume of prescriptions for antidepressants Overdose data Alcohol use per capita Employment Suicide rate fell 13.5% from 12.38 to 10.71/100K Greater fall in women Antidepressant prescriptions rose from 35m to 144m pa 69% of increase was SSRIs (Grunebaum et al, J Clin Psych 2004;65:1456-62).

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


12 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)

13 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)

14 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

15 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

16 Comparative side effects of antidepressants

17 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

18 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

19 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

20 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 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)

21 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).

22 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)

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

24 Relapse prevention

25 Imipramine Study Frank E et al, Arch Gen Psychiatry 1990;47:1093-9 n=128

26 Long-term studies 6 months1 year2 years + imipramine 1 fluoxetine 2 citalopram 3 paroxetine 4 sertraline 5 escitalopram 6 duloxetine 7 1. Frank E et al Arch Gen Psychiatry. 1990;47:1093-99 5. Wilson et al, 2003;182:492-7 2. Reimherr F et al Am J Psychiatry 1998;155:1247-53 6. Kornstein S et al J Clin Psych 2006; 1767-75 3. Franchini et al J Clin Psychiatry 1999;60:861-5 7. Detke M et al Euro Neuro Psych 2004;457-70 4. Reynolds C et al New Engl J Med. 2006;1130-8

27 Positive long-term studies 6 months1 year2 years + imipramine 1 fluoxetine X2X2 citalopram X3X3 paroxetine ?4?4 sertraline X5X5 escitalopram 6 duloxetine 7 1. Frank E et al Arch Gen Psychiatry. 1990;47:1093-99 5. Wilson et al, 2003;182:492-497 2. Reimherr F et al Am J Psychiatry. 1998;155:1247-53 6. Kornstein S et al J Clin Psych. 2006; 1767-1775 3. Franchini et al J Clin Psych. 1999;60:861-865 7. Detke M et al Euro Neuro Psych. 2004;457-470 4. Reynolds C et al New Eng Jour of Med. 2006;1130-1138

28 Long-Term Studies DrugDosing RegimeResultsNotes imipramine (160-200mg) 12 weeks treatment/ 17 weeks continuation/ 3 years maintenance Relapse prevention over 3-5 years Includes IPT fluoxetine (20mg) 12-14 weeks treatment/ 50 weeks maintenance Positive for 38 wks, no sig diff at 62 wks 4 treatment arms citalopram (20-40mg) 6 weeks treatment/ 4 months continuation/ 24 months maintenance 50% recurrenceNo placebo control. 20mg maint dose sertraline (50-200mg) 8 weeks treatment/ 16-20 weeks continuation/ 100 weeks maintenance No significant difference to placebo at 100 weeks Pts over 65 paroxetine (10-40mg) 8 weeks treatment /16 weeks continuation/ 2 years maintenance Significant difference between groups seen only after adjustment Pts 70 yrs or over. Includes IPT.

29 Review of PREVENT Study Prevention of Recurrent Episodes of Depression with Venlafaxine ER for Two Years

30 Long-term treatment: venlafaxine XL PREVENT Study Acute (10 weeks) Continuation (6 months) Maintenance A (1 year) Maintenance B (1 year) Venlafaxine Placebo Responders non-responders Discontinue Responders Simplified design adapted from Kornstein SG et al. Presented at the 6th International Forum on Mood and Anxiety Disorders, Vienna, Austria, November 29-December 1, 2006.

31 PREVENT: Primary Objectives Acute Phase (10 weeks): Demonstrate venlafaxine XL efficacy in achieving satisfactory therapeutic response/remission in MDD patients following 10 weeks of treatment Continuation Phase (6 months): Demonstrate venlafaxine XL efficacy in sustaining response (satisfactory therapeutic response/remission) - in MDD patients who achieved these responses in the acute phase Maintenance Phases (2 consecutive 12-month phases): Compare venlafaxine XL and placebo in preventing recurrence of depression in MDD patients who are responders after previous phases of venlafaxine XL treatment Keller M et al Poster presented at ACNP Puerto Rico December 2004

32 Major Inclusion/Exclusion Criteria Inclusions: 3 major depressive episodes in lifetime, including 2 episodes in past 5 years* HAM-D 17 of 18 at baseline Symptoms present for 1 month Exclusions: Previous failure to respond to an adequate trial of venlafaxine In previous 3-years, failed 3 adequate trials of 2 classes of antidepressants *Interval 2 months between the end of previous episode and beginning of current episode. Keller M et al Poster presented at ACNP Puerto Rico December 2004

33 Response/Remission definitions Satisfactory Therapeutic Response Total HAM-D 17 12 or minimum 50% reduction of total HAM-D 17 compared to the acute baseline Remission HAM-D 17 score 7 Sustained Remission HAM-D 17 score 7 sustained on two consecutive visits Keller M et al Poster presented at ACNP Puerto Rico December 2004

34 Definitions used in post hoc analysis <225mg/d Doses <225mg in acute or continuation phase Recurrence defined as: Patients who had total score of HAM-D 17 >12 and a HAMD 17 reduction no more than 50% from acute- phase baseline at two consecutive visits, or at the last valid visit in case of early discontinuation Or Dose >225mg Kornstein S et al Poster presented at IFMAD Vienna November 2006

35 Probability of recurrence – combined maintenance phases by Dose Subgroup ( 225 mg) Kornstein S et al Poster presented at IFMAD Vienna November 2006

36 Summary 1-7+8 6 months1 year2 years + imipramine 1 fluoxetine 2 No significant difference from placebo at 62 weeks citalopram 3 No placebo control paroxetine 4 No significant difference over placebo (unless adjusted for IPT) sertraline 5 No significant difference to placebo at 100 weeks escitalopram 6 no published data Duloxetine 7 no published data venlafaxine 8

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

38 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

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

40 Summary of dose-response curves

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

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

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

44 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)

45 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

46 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

47 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

48 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

49 Paroxetine discontinuation

50 MedEd technique

51 STAR*D Sequenced Treatment Alternatives to Relieve Depression Largest ever RCT in depression Independent, funded by NIMH Focus on REMISSION Inclusions: MDD, chronic depression, co-morbidities (61.5%) Exclusions: OCD, eating disorders, bipolar, prior non-response, pregnant, breast-feeding, recent hospitalisation for SM, psychotic depression Drugs/strategies chosen as safest, easiest and most used

52 STAR*D Level 1 – open SSRI Remitters followed up over one year Non-responders or intolerant entered level 2 Some would also have been partial responders Patients had choice in which type of strategy Level 2 – switch or augment Level 3 – switch or augment Level 4 – switch


54 STAR*D – conclusions Level 1: Give people 8/52 to respond Push citalopram to 40(-60)mg/d Level 2: Switching to another SSRI is as effective as other switches Switching may be better if no response Augmentation may be better if partial/incomplete response but could actually just be delayed SSRI response (other RCTs) Level 3: No significant difference between mirtazapine or nortriptyline in response or tolerability Augmentation looks better Dont know if these would have been better earlier Level 4: Response limited

55 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

56 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)

57 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).

58 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

59 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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