1 Treatment and Outcome of Refractory DepressionDr Noel Kennedy St Edmundsbury & SPUH 11-March-17

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3 Depressive disorders are the most common reason for admission to a psychiatric unit in Ireland

4 60-95% recurrence 8% unnatural death 50% time symptomatic(Lee & Murray 1988, Mueller et al 1999, Kennedy et al 2003)

5 More years with disability than any other medical/psychiatric disorder(Murray & Lopez 1996) Estimated economic cost of $50 billion p.a.

6 Unipolar Depression: OutcomeRecovery (O’Leary et al, 2000) - (50%-6months, 70-75%-1year, 80-85%-2 years) Recurrence (Mueller et al, 1999) - (25%-1 year, 40%-2 years, 60+%-5 years) Suicide (Osby et al, 1999) 7-9% hosp, 20+ OR Psychosocial Impairment (Kennedy et al, 2007) - (25% work, 30-35% marital, 40-60% social)

7 Long-Term Outcome Studies of DepressionRecent long-term outcome studies No. subject (N) Years follow-up Subjects followed-up (%) Non recovery (%) Recurred Unnatural death follow-up (%) Lee & Murray (1988) 89 18 99 10 95 Kiloh et al (1988) 145 15 93 12 76 Surtees & Barkley (1994) 80 100 60 Kennedy et al (2003; 2004) 70 9-11 8 66 3 Toshiaki et al (2000) Kanai et al (2003) Kolma et al (2008) 90 163 6 5 96 - 13 43 71 2 NIMH CDS Judd et al (1998) 442 77 11.5b 85c N/Ad

8 Depression and subsyndromal symptoms over 10-year follow-up (Kennedy et al, 2004)

9 Residual Symptoms Predict Recurrence

10 Subsyndromal depression50-60% of follow-up time spent with symptoms Residual symptoms predict relapse Residual symptoms impair social functioning) (Paykel et al, 1995; Judd et al, 1998, Kennedy et al, 2004)

11 Recent Primary Care Outcome StudiesOutcome still relatively poor - Vantnaa 5-year Outcome Finland (Holma et al 2008) - 163 OPD, longitudinal, 88% remission, 70% recurred - PD, dysthymia, length of episode predicted outcome Primary care/early in course still problematic - Japanese 6-year follow-up n=95, OPD mainly 1st episode 85% recovery, 42% relapse, better psychosocial (Furukawa et al, 2000; Kanai et al, 2003) - Finnish 5-year 1ry care (Riihimaki et al, 2011) 70% remission, >1/3rd relapsed, 58% symptomatic

12 Summary of Studies Non-recovery from index 10-20%Recurrence rates 60-70%, psychosocial Symptomatic 50-60%, syndromal 15% Unnatural death rate 5-8% Predictors severity, PD, length of episode, previous episodes

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14 Refractory Depression: DefinitionsFailure to respond fully to >1 or several antidepressants (30++%) Chronic duration <2 years (10%) - least likely to be effectively treated Partial response also a problem (>40%)

15 Levels of Treatment Resistance (Thase et al 2008)Stage 1: Failure of one adequate trial of an antidepressant Stage 2: Stage 1 and non response to alternative antidepressant Stage 3: Stage 2 plus failure to respond to Lithium Stage 4: Stage 3 plus failure to respond to a MAOI Stage 5: Stage 4 plus failure to respond to ECT

16 Assessment and Management of TRDThorough history, diagnosis, predictors and Tx (LIFE Chart, MSM, SAPAS) Prescribed medications or medical illness may cause depression Review precipitants of depression (e.g. bereavement, early life trauma, marital or family dysharmony, social factors) Consider comorbidity (anxiety disorders, substance abuse, dementia) and personality disorder (cluster c) Misdiagnosis (BPI >5%, BPII 10%+) Chronicity/cognitive change

17 Affective Spectrum Unipolar Bipolar Bipolar Spectrum 5% 3% <1%Family Hx Early onset Psychosis

18 Bipolar Spectrum BP II:- False Unipolar Bipolar Spectrum Disorder- More like UP than BP - W>M - Clinical severity, rapid cycling, co-morbidity - Depressions with brief hypomanias False Unipolar % Bipolar Spectrum Disorder

19 Structural MRI: Unipolar Depressionwhite matter hyperintensities - late onset - DWML>>PVL - worse prognosis - poor treatment response - vascular depression (Fava et al, 2006)

20 Depression Comorbidity (NESARC)

21 Pharmacology of TRD

22 TRD Management: PharmacologicalAntidepressants remission (30%) Partial response a problem (40%) Length of treatment important (4-8 weeks) Not all antidepressants are equal (meta-analysis, % achieving full remission, TRD studies NNT high) Consider symptoms Length of continuation/maintenance treatment (Kennedy; Lam; Nutt & Thase, 2007)

23 Consider Symptoms and Side EffectsNE 5HT2c Attention Drive Appetite Mood Sleep Loss of pleasure Obsessions Anxiety Cognitions

24 Consider Symptoms and Side EffectsNE 5HT2c Mood Sleep Loss of pleasure Attention Drive Appetite Obsessions Anxiety Cognitions DA

25 Consider Symptoms and Side EffectsNE 5HT2c Venlafaxine (150+) Duloxetine TCA MAOI/RIMA Paroxetine Venlafaxine (225+) Reboxetine Mirtazepine Bupropion Methylphenidate Pramipexole D2/D3 SSRI Olanzapine Clomipramine DA

26 Management of TRD: OptionsOptimize length of treatment (6-8 weeks if partial response) High dose treatment if linear dose response (especially TCA & venlafaxine) Switch class of antidepressants Augmentation of antidepressant Consider antidepressant combinations or ECT

27 STAR*D (Sequential Treatment Alternatives to Relieve Depression)6-year naturalistic study, 4000 enrolled, $35 m, NIMH - Step 1 Citalopram 60mgs, 3 months 27.5% remission - Step 2 switch (Sert, Ven, Bup) or augment (Bup>Bus) augment 30%>switch 25%, CBT - Step 3 >40% non-remitted after 2 trials (Nor>Mir) 13-25% remission (T3>Li) augment > switch - Step 4 Venlafaxine/Mirt 14% > Tranylcypromine 7%

28 STAR*D (Sequential Treatment Alternatives to Relieve Depression)Remission - female gender - employed - higher socioeconomic/income Non-remission - medical/psychiatric co-morbidity - premorbid functioning - episode length

29 Management of TRD: AugmentationLevel I: (Meta or RCT with Placebo) - low dose lithium ( mgs, >0.6mmol/l) 50% response within 1 week - Second: low dose atypical antipsychotics (Olanzapine, (Level 1), Risper and Quet (level 2) Level 2: (RCT Placebo or Active Comparison) - Bupropion, Triiodothronine (T3), Psychostimulants Level 3: (Uncontrolled Trial (>10 subjects) - Modafanil, Methylphenidate, lamotrigine, pramipexole (level 3- BPAD!!) - Combinations (ven/mir, TCA/SSRI, MAOI/TCA Negative data: (tryptophan, pindolol, buspirone)

30 Novel Augmentation ApproachesBupropion (Zyban 150) mgs/day - ↑Nad/Dop safe/alerting, ↑energy - Augmentation (SSRI or dual) or on own - Used in US to improve sexual s/e SSRIs - Side effects – agitation, tremor, insomnia - NB rare convulsions dose related - NB do not use with MAOI can be fatal - Not great for anxiety Modafanil (Provigil) mgs/day headache, ↑BP Omega-3-fatty acids (EPA 1.5 gms/day ) Dexamethasone 4 mgs/day X 4 days

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32 Psychotherapy for TRD Cognitive Behavioural Therapy (Level 1)- Few RCTs 158 chronic patients randomized to CBT (26+ sessions) or TAU. Weakening benefit for 3.5 years (Paykel et al 1999; 2005) CBASP (Cog Beh Analysis Sys Psych McCollough) - Chronic depression (20+ sessions) relationship prob solving, RCTs disappointing no better than pharm/BSP 2 recent trials (Kocsis et al, 2009; Schromm et al, 2009) Interpersonal Therapy (Weissman) Level 2 + meds

33 Physical Treatments ECT (75% remission), less effect TRD, relapserTMS left dorsolateral prefrontal (level 2), very safe, little effect TRD or severe VNS open label, 40% TRD increasing, hoarse Surgery DBS, ant cing, subcaud tract Light Therapy, 10,000 lux am, winter depression

34 Chronic Depression Episode lasts more than 2 yearsLow grade “dysthymic like” state (Keller et al 1987) Poor long-term social functioning (Kennedy et al, 2007) 70+% risk of co-morbid personality disorder – dependant (Tyrer et al, 2004)

35 Chronic Depression: TreatmentAgree goals with patient – slow gradual improvement over 1 year+, no magic cures May need intensive multidisciplinary approach as an inpatient (OT, CBT, Ind + Gp Psy, FT, IPT) LIFE , Episodes, Personality, Precip, Tx pharm + psych Psychoeducation Optimise pharmacological treatments

36 1. Treatment in Chronic TRDAll refractory depressives over 10-years Cambridge TRD (Kennedy & Paykel, 2004) Mean episode length (41 months) Best response - High dose TCAs and SNRIs - Combination antidepressants - Lithium augmentation - ECT - CBT Over 80% response but few asymptomatic

37 2. Treatment in Chronic TRDTertiary refractory depressives Maudsley Unit less tertiary (Fedaku et al, BJPsych, 2012) 118 (79%) prospective longitudinal follow-up mean 39 months) 60% remission (75% follow-up time symptomatic) 55% of those remitting relapsed Predictors - Severity, social support and education MAOIs and Duloxetine predicted remission

38 Mood Disorders Units (MDU)Given the morbidity associated with depression little data regarding operation or outcome of MDU Gordon Parker, Sydney “Black Dog Institute” - detailed assessment and 3 month follow-up - access to online and group psychoeducation Gene Paykel, Cambridge intensive inpatient (3 months) and daypatient treatment (3 months) Tony Cleare, Maudsley intense inpatient treatment (6 months)

39 Mood Disorders Units (MDU)General principles - detailed initial assessment (semi-structured interview) - psychoeducational programmes - access to psychotherapy (individual and group) - High dose pharmacotherapy (augmentation) - continuity of care (6-12 months) - link clinical care and research

40 “ Finding the right balance of treatment whether lithium, antipsychotics, SSRIs or other kinds of treatment can be a very hit and miss heuristic process requiring great patience and careful, classy, caring doctoring” Stephen Fry

41 St Edmundsbury Mood Disorder ProgrammeInpatient 4-6 weeks:- NB Avoids Institutationalism - Assess episodic LIFE, SAPAS, Tx, precip/perp - Agree care plan - Programme generic + specialized (GP CBT, IPT, Mind, RO, BA) - Individual work (OT, IPT, FT, CBT, DP, Pharmacist 60%+) Daypatient 3-6 months (>1 prog):- - RO, CFT, BAD, CBT, ACT, Mind, HSE, RTPD also SPUH progs Outpatient care (>1 year) - Continuity (88% 1st episode >1 year follow-up) -

42 Integrated Service Inpatient Unit (52 Beds) Day-Patient Unit(40 places) Dean Clinic (3 Days per week)

43 Integrated Service SubspecializationDr Prasad MDT Mood/BPAD Dr Morgan MDT Mood/Dual Dx Dr Kennedy MDT Mood/Refractory Depression

44 SEH Inpatient MDU ProgrammeMonday Tuesday Wednesday Thursday Friday 10 Anxiety L All 10 Depress L 10 Managing Change L All 10 Psychol GP All 10 Goal Setting All 11 Healthy Eat 11.30 Stress Man Ref 11 Relaxation All 11 Info Centre All 11 Exercise 12 CBT GP Ref 11.30 Induction All New 12 Roles in Tran GP All 12 Inpatient Psychotherapy GP Ref 11 Art/Music Class All 2 BADep GP All 4 Exercise All 2 Pilates All 2.30 Social GP All 3.15 Relaxation All 2 Healthy Self Esteem All 3 Mindfulness GP All 6 Twilight All 2 CBT L All 3 Pilates All 4 Relaxation All 2.30 Relaxation + Mindfulness All

45 St Edmundsbury MDU: Operation and Outcome18-month longitudinal follow-up:- - All first-episode depression admissions ( ) (n=137) - Semi-structured interview (SCID, SAPAS, LIFE) - LIFE weekly 18-month follow-up of outcome (100%) Baseline (MSM):- - 75% treatment resistant, 42% MSM resistant - 33% chronic (>2 years) - 56% PD, 40% psychiatric co-morbidity - 40% tertiary referrals

46 Inpatient MDU Individual TreatmentIntervention Family/Couple/IPT Occupational Therapy CBT Psychotherapy Social Worker n (137) 66 65 46 40 9 % 48 47 34 29 7

47 Inpatient Pharmacological TreatmentPharmacological Agent SSRI SNRI TCA Augmentation Lithium Bupropion Antipsychotic Combination ECT Baseline % 56 39 4 32 12 16 1 Discharge % 21 64 15 74 25 10 22 33 11

48 St Edmundsbury MDU: OutcomeRemission and Relapse:- - 95% remission overall 73% within 6 months 88% within 1 year - 33% of those remitted had a full relapse Predictors:- - remission = male gender, length of episode, resistance - relapse = personality disorder, length of episode

49 Symptomatic Outcome after First Episode Depression (NIMH CDS, Kanai et al 2005)

50 Symptomatic Outcome after MDU First Episode Depression Treatment

51 Conclusions Despite high levels of morbidity little data exists about treatment of refractory depression Refractory depression is likely to need intensive and lengthy psychoeducational, psychological and pharmacological treatments Good continuity of care leads to a more consistent response in depression Intensive specialized treatment appears to impact on percentage remitting over time and symptomatology but less or relapse risk. Need for further approaches given co-morbidity (eg schema therapy)