Overview and update in developments for the treatment of depression

1. Overview and update in developments for the treatment of depression Anna Grunze Consultant East CMHT, Northumberland, Tyne and Wear NHS Foundation Trust Anna.Grunze@ntw.nhs.uk

2. Overview • Drug treatment of depression • Suicidality – impact and prevention • Discussion

3. Drug treatment of depression • When is it appropriate to use an antidepressant? • Which antidepressant should you use? • How long should you treat for?

4. Drug treatment of depression • When is it appropriate to use an antidepressant?

5. The stepped-care model Focus of the intervention Nature of the intervention STEP 4: Severe and complex1 depression; risk to life; severe self-neglect Medication, high-intensity psychological interventions, electroconvulsive therapy, crisis service, combined treatments, multiprofessional and inpatient care STEP 3: Persistent subthreshold depressive symptoms or mild to moderate depression with inadequate response to initial interventions; moderate and severe depression Medication, high-intensity psychological interventions, combined treatments, collaborative care2, and referral for further assessment and interventions STEP 2: Persistent subthreshold depressive symptoms; mild to moderate depression Low-intensity psychosocial interventions, psychological interventions, medication and referral for further assessment and interventions STEP 1: All known and suspected presentations of depression Assessment, support, psycho-education, active monitoring and referral for further assessment and interventions 1,2 see slide notes

6. WWW.BAP.org.uk

7. Categories of evidence for causal relationships and treatment I - Meta-analysis, at least one large good RCT or replicated smaller RCTs II - Small non-replicated RCTs, at least one controlled study without randomisation or evidence from at least one quasi-experimental study III - Non-experimental descriptive studies IV - Expert committee reports or opinions and/or clinical experience of respected authorities Proposed categories of evidence for non-causal relationships I - Large representative population samples II - Small, well designed, but not necessarily representative samples III -Non-representative surveys, case reports IV - Expert committee reports or opinions and/or clinical experience of respected authorities Strength of recommendations A - Directly based on category I evidence B - Directly based on category II evidence or extrapolated from I C - Directly based on category III evidence or extrapolated from I or II D - Directly based on category IV evidence or extrapolated from I, II or III S - Standard of good practice

8. Diagnosis of depression: ICD-10 criteria • Key symptoms (must have at least 2 of these) • Persistent low mood • Loss of interest or pleasure • Fatigue or low energy • If any of above then ask about: • Disturbed sleep • Poor concentration or indecisiveness • Low self confidence • Poor or increased appetite • Suicidal thoughts or acts • Agitation or slowing of movement • Guilt or self blame • 4 symptoms = mild • 5-6 = moderate • 7+ = severe (+/- psychotic symptoms)

9. Diagnosis of depression: Grades of severity • 4 grades of severity used in the guideline: • Sub-threshold depression (minor depression) • significant depressive symptoms below the DSM-IV MDD threshold, including ICD-10 mild depressive episode with only four symptoms; • Mild major depression (Mild MDD) • symptoms barely meet the minimum criteria and mild functional impairment; • Moderate MDD • more than minimum number of symptoms and moderate functional impairment; • Severe MDD • most symptoms are present and marked or greater functional impairment.

10. Indications for antidepressants:Duration and severity of depression guides: treatment choice (A) • Antidepressants are a first line treatment for: • moderate and severe MDD in adults (A), • Sub-threshold depression that has persisted for 2 years or more (A). • Antidepressants are an option for short duration mild MDD in adults (B) especially if: • there is a history of moderate to severe recurrent depression (D) • the depression has persisted for more than 2–3 months (D). • Antidepressants are not a first line treatment for: • short duration sub-threshold depression in adults (A) but consider if: • the depression persists for more than 2–3 months (C) • there is a prior history of moderate to severe recurrent depression (D)

11. Drug treatment of depression • Which antidepressant should you use?

12. 29 • Others: • Buproprion – UK licence for smoking • Buspirone – UK licence for anxiety

13. Choosing an antidepressant Efficacy • Tolerability Cost, Preference Safety

14. Choosing between antidepressants Difference in efficacy Need to tailor choice to circumstance • Difference • in tolerability Difference in cost Difference in safety

15. Choosing between antidepressants Difference in efficacy Primary care, mild moderate, ‘uncomplicated’ • Difference • in tolerability Difference in cost Difference in safety

16. Choosing between antidepressants Difference in efficacy Severe, failed previous treatment, suicidal • Difference • in tolerability Difference in cost (Difference in safety)

17. Severity of Depression and Response Per cent response Baseline HAM-D From Angst (1993)

18. Choice of antidepressant drug • Match antidepressant to individual patient as far as possible (S) • see Table 5 • In the absence of special factors: • choose antidepressants that are better tolerated and safer in overdose (S). • most evidence for SSRIs • with other newer antidepressants these are first line choices • Older TCAs reserved for if first line drug treatment has failed (D) • MAOIs not first line and should only be initiated by practitioners with expertise in treating mood disorders (D). • In more severely ill patients, and where maximising efficacy is of overriding importance, consider: • an older TCA, venlafaxine (≥ 150 mg) or escitalopram (20 mg)

19. Factors to consider in choosing an antidepressant • patient preference (B), • associated psychiatric disorder that may specifically respond to a particular class of antidepressant (e.g. OCD and SRIs) (B), • previous treatment response to a particular drug (D), • tolerability and adverse effects of a previously given drug (D), • likely side effects (e.g. sedation, sexual dysfunction, weight gain) (C), • low lethality in overdose if history or likelihood of overdose (D), • concurrent medical illness or condition that may make the antidepressant more noxious or less well tolerated (C), • concurrent medication that may interact (C), • a family history of differential antidepressant response if choosing between a TCA and MAOI (C).

20. Are SNRIs better than SSRIs? Papakostas, G. I., Thase, M. E., Fava, M., et al (2007) Biological Psychiatry, 62, 1217-1227. NNT=24

21. Fatal toxicity of serotonergic and other antidepressant drugs “1993-1999, Single ingestions + alcohol:England,Wales & Scotland” FTI= fatal toxicity index expressed as deaths per million prescriptions. Buckley N and McManus P, BMJ 2002 325 : 1332-1333

22. Painful Symptoms Are Highly Correlated With Depression 50 Limb pain N=18,980 Backaches 40 Joint/articular pain Gastrointestinal pain Headaches 30 Any pain % Frequency 20 10 0 Normal Mood Major Depressive Disorder (MDD) Ohayon MM, Schatzberg AF. Arch Gen Psychiatry. 2003;60(1):39-47.

23. 10 OR > 1; INCREASING CHANCE OF NOT ACHIEVING RESPONSE 8 6 Odds ratio (OR) +/- 95% CI 4 2 0 No pain Mild Moderate Severe OR =1; response to therapy Pain severity at baseline Severity of pain and response to SSRI therapy N=573 SF-36 scale Bair MJ et al. Psychomsomatic Med 2004; 66:17–22.

24. Agomelatine 25-50 mg n = 116; Placebo n = 119 Repeated measures ANOVA

25. Ketamine i.v. in TRD • DB RCT with crossover design • 18 subjects with MDD being drug free for 2 weeks received a single intravenous infusion of either ketamine hydrochloride (.5 mg/kg) or placebo on 2 test days one week apart. • Primary outcome measure: 21-item HDRS • Subjects receiving ketamine showed significant improvement in HDRS compared with subjects receiving placebo within 110 minutes which remained significant for one week. The effect size for the drug difference was very large (d = 1.46 [95% confidence interval, 0.91-2.01]) after 24 hours and moderate to large (d = 0.68 [95% confidence interval, 0.13-1.23]) after 1 week. • AE occurring more commonly with ketamine were perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido. In no case did euphoria or derealization/depersonalization persist beyond 110 minutes Zarate et al., 2006 * indicates P<.05; †, P<.01; ‡, P<.001.

26. Drug treatment of depression • How long should you treat for?

27. Treatment trial duration • Lack of significant improvement after 2–4 weeks treatment substantially reduces the probability of eventual sustained response (A). • After 4 weeks adequate treatment: • if there is at least some improvement continue treatment with the same antidepressant for another 2–4 weeks (B), • if there is no trajectory of improvement undertake a next-step treatment (B); • in patients who have failed a number of treatments consider longer trials (D) • After 6–8 weeks adequate treatment: • if there is moderate or greater improvement continue the same treatment, • if there is minimal improvement undertake a next-step treatment (B) • in patients who have failed a number of treatments consider longer trials before changing treatment (D).

28. Choice of antidepressant • Continuing medication • Advise use of antidepressants for at least 2 years. • Maintain level of medication at which acute treatment was effective (unless there are adverse effects) if: • the person has had two or more recent episodes of depression which caused significant functional impairment • they have other risk factors for relapse • the consequences of relapse are likely to be severe. • After 2 years • Re-evaluate treatment with the person, taking into account age, comorbidities and other risk factors; thereafter reevaluate as regularly as needed.

29. Overview • Suicidality – impact and prevention

30. The extent of suicidality • Lifetime suicide risk of 6% for affective disorders (metaanalysis of 27 mortality studies, Inskip et al, 1998) • SMRs for suicide: 20.9 (males) and 27.0 (females) for subjects who had ever been hospitalized for unipolar depression (Ösby et al., 2001)

31. What constitutes “suicidality” ? • Luckily, completed suicide and suicide attempts are still a rare event- and thus cannot be captured as a significant (and unethical) outcome in controlled trials • As a consequence, weaker outcomes as “suicidality” are commonly used, but what is “suicidality”? • Suicidal ideation • Suicidal behavior • …. ?

32. Pro AD’s increasing suicide risk • Increased suicidality (and suicide events) in some individuals early in AD treatment (Healy and Whitaker, 2003) • Meta-analysis of 702 randomized controlled trials including more than 87,000 depressive and other psychiatric patients showed a significantly increased risk of suicide attempts (OR, 2.28), but not of completed suicides in patients taking SSRIs compared with placebo (Fergusson et al, 2005)

33. Suicide rates vs. SSRI sales, 1980–2000 Ludig & Marcotte, 2005

34. Contra AD’s increasing suicide risk • Several epidemiological studies show reduction of suicidality in association with antidepressant prescription (e.g.,Carlsten et al., 2001; Hall et al., 2003; Isacsson et al., 1997; Isacsson, 2000; Ohberg et al., 1998; Rihmer et al., 2000; Ludwig & Marcotte 2005) • However, open studies and population-based studies can easily be subject to several biases and errors in interpreting results (Möller, 2006)

35. Contra AD’s increasing suicide risk • Following up on FDA warnings, Simon et al. (Simon et al., 2006) analyzed computerized health plan records from a total of 82,285 episodes of antidepressant treatment between 1 January 1992 and 30 June 2003 • Identifying death by suicide and serious suicide attempts, they found that the risk of suicide attempts was highest in the months before starting antidepressant treatment and declined progressively after starting medication.

36. Suicidality risk in RCTs with AntidepressantsMeta-analysis of 372 double blind randomised placebo controlled trials • 99231 adults assigned to antidepressants or placebo • For participants with non-psychiatric indications, suicidal behaviour and ideation were extremely rare. For those with psychiatric indications, risk was associated with age. • When age was modelled as a continuous variable, the odds ratio for suicidal behaviour or ideation declined at a rate of 2.6% per year of age (−3.9% to −1.3%, P=0.0001) and the odds ratio for suicidal behaviour declined at a rate of 4.6% per year of age (−7.4% to −1.8%, P=0.001) Stone et al,2009

37. Conclusions • Major depression of at least moderate severity warrants treatment with ADs • It is less clear how effective ADs are for milder depression • Choice between ADs depends on multiple factors • There are clear differences in side effect profiles • It is less clear whether there are differences in efficacy • if there are then these are small and most evident in severely ill patients

38. Conclusions (cont) • Most people who respond start doing so in the first 2-4 weeks • ADs are potent prophylactic agents • Clear evidence from epidemiological studies is in favor of reduced suicide rates with antidepressant treatment

39. Thank you !