Management of Refractory Depression

Dr. Josh Geffen Psychiatrist Contents • Diagnosis – Defining depression – Clinical classification • Management – Refractory depression • Treatment resistant depression • Response v remission – Management by sub-type • Non-melancholic depression • Melancholic Depression – Unipolar v bipolar – Psychotic depression

27/05/17 Diagnosis

27/05/17 Essence of major depression

High prevalence group of disorders characterized by • morbid and pervasively negative mood • depressive cognitions • neuro-vegetative disturbance • variable degrees of psychomotor change

27/05/17 Course of major depression

Typically follow a chronic fluctuating or recurrent episodic course • High morbidity • Significant mortality • Often associated with psychiatric co-morbidity • Often associated with medical co-morbidity

27/05/17 The Classificatory Debate

• “ lack of a highly reliable or valid classificatory system has significant and practical clinical consequences, particularly in primary care where the full range of depression presents” • “concern is whether depression should be classified u3sing dimensions or categories” • clinicians required to make a categorical decisions – antidepressants or not, specialist referral or not

NICE Clinical Guidelines, No. 90. 27/05/17 National Collaborating Centre for Mental Health (UK). Leicester (UK): British Psychological Society; 2010 Essence of major depression

♦ Depressed mood - morbid and pervasive ♦ Depressive cognitions – hopelessness (-ve future) – helplessness (-ve environment) – worthlessness, guilt (-ve self) ♦ Neurovegetative disturbance – sleep, DMV, anhedonia – appetite, wt – energy, concentration, libido ♦ Psychomotor changes - agitation/retardationy

27/05/17 Dimensional v Categorical Classification • Categorical model (hierarchical model which is clinically useful) – a group of disorders (incorporates bipolarity) • non-melancholic depression (‘reactive’) – with anxiety (internalising) – with hostility (externalising) • melancholic depression (‘endogenous’) – unipolar v bipolar disorders – atypical depression – psychotic/agitated depression (melancholia + psychosis)

27/05/17 Dimensional v Categorical Classification • Dimensional model (DSM IV & ICD 10) – A single disorder (bipolarity separate) • major depressive disorder – single episode v recurrent – Severity mild moderate severe • DSM 5 specifiers includes mixed features – anxious distress – melancholic features – atypical features* – mood-congruent psychotic features – mood-incongruent psychotic features* – catatonia* – mixed features* – peripartum onset* – seasonal pattern 27/05/17 DSM V – Grief v Depresison

• Responses to a significant loss - bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability - may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss which may resemble a depressive episode • A major depressive episode may occur in addition to the response to a significant loss • Decision requires the exercise of clinical judgment based on history and cultural norms for the expression of distress

27/05/17 Depression-like states

• Sub-syndromal depressive symptoms – Acute • Grief/Adjustment disorder • Substance induced mental disorder • Sub-syndromal episode of primary mood disorder – Chronic • Persistent depressive disorder (replaced dysthymia & incorporated chronic residual symptoms of MDD) • Cyclothymia (disorder or sub-syndromal bipolarity?) • Substance induced mental disorder

27/05/17 Clinical sub-typing of depression • Major Depression – Melancholic • unipolar v bipolar • ? with psychotic or agitated features • atypical – Non-melancholic • with anxiety (internalising) • with hostility (externalising)

27/05/17 Recurrence Becomes More Likely With Each Episode of Depression

First episode1-3 >50%

Second episode2 ≈70%

Third + episode2 ≈85%

0 20 40 60 80 100 Recurrence risk (%*) following recovery during long-term follow-up*

*Patients were followed for 3 to 15 years following recovery from previous episode. 1. Judd LL, et al. Am J Psychiatry. 2000;157:1501-1504. 2. Mueller TI, et al. Am J Psychiatry. 1999;156:1000-1006.3. 3. Keller MB, Boland RJ. Biol Psychiatry. 1998; 44:348-360. 27/05/17 Stressful Life Events as a “Trigger” for Depression Progressively Declines

10

8 Risk (%) of depression onset per month “Kindling” Phenomenon 6 With increasing Risk* depressive episodes: 4 Risk of depression

2 Association with Likelihood of recent life stress* stressful life events 0

0 1 2 3 4 5 6 7-8 9-11 No. of previous depressive episodes 27/05/17 *Odds ratio for depression given at least one stressful life event. Kendler KS, et al. Am J Psychiatry. 2000;157:1243-1251. Response v Remission

• 1/3 of patients fail to achieve an adequate response to therapy1,2 • Health, social & economic burden of refractory depression • risk of relapse • morbidity & mortality • health care costs • carer burden • social functioning • productivity • Remission optimal but not always feasible

27/05/17 Refractory Depression – usually 3 AD trials are needed before the majority of patients respond to the point of remission 1 – patients aim for recovery .... doctors aim for remission2

27/05/17 Def’n of Refractory Depression (TRD) – No agreed definition of treatment resistance

• Minimum – depression that does not fully remit with initial treatment • Standard – “major depression (not 20 to substance or medical condition) that has failed to respond, or to sustain response to an adequate trial of standard antidepressant”1 • Maximum – Failure to respond to at least two antidepressants from different classes in conjunction with at least one recognised psychotherapy

27/05/17 Residual Symptoms and Number of Episodes May Influence the Course of

Median Illness Previous weeks Recovery episodes N well 1.0 Asymptomatic 1–3 121 224.0 Asymptomatic 3+ 34 79.0 0.8 Residual SSD 1–3 57 34.0 Residual SSD 3+ 25 28.0 0.6

0.4

0.2

0 0 50 100 150 200 250 300 350 400 450 500 Survival Distribution Function DistributionSurvival Weeks to First Prospective Relapse to any Depressive Episode

MDD=Major depressive disorder; SSD=Subsyndromal symptoms of depression; Survival distribution function=Cumulative proportion of cases surviving to given time interval. 27/05/17 Judd et al. J Affect Disord 1998;50(2-3):97-108. Copyright Elsevier (1998). Relapse if remission is not achieved? % of Patients Who Relapsed (2-year Follow-up Study) 100 80 *p<0.0001 * 70 67.6% 60 50 40 30 Patients(%) 20 15.2% 10 (n=71) (n=112) 0 Patients in Patients in Partial Complete Remission Remission 27/05/17 Pintor et al. J Affect Disord 2003;73(3):237-44. Longer term treatment outcomes: value of effective Rx • Rapid remission most important predictor long- term (N=196, 2-year study)1 • Longer previous episode reduced the likelihood of recovery by 37% (N=250, 2-year study)2 • Lower relapse rates if in remission at follow-up (N = 2238 STAR*D with 12 month follow up)3 • Lack of response to first antidepressant predicts future treatment resistance (N=702)4

1. Szadoczky et al. J Affect Disord 2004;83(1):49-57. 2. Spijker et al. J Affect Disord 2004;81(3):231-40. 27/05/17 3. . Rush et al Am J of Psychiatry November 2006. 4. Souery et al. J Clin Psychiatry 2007; 68(7):1062-70. Partial response increases relapse

27/05/17 Risks of refractory depression

• Greater risk of relapse/recurrence1-3 • More chronic depressive episodes1 • Shorter durations between episodes1 • Continued impairment in work and relationships4 • increase in all-cause mortality5 and morbidity and/or mortality with stroke,6 diabetes,7,8 MI,9 CVD,10 CHF,11 HIV,12 etc • Sustained risk of suicide13 • Long term remission ifficult to achieve and maintain14 • 80% with remission from multiple treatments relapse < 1 year • Protracted illness only 40% recovery over 10 years

1.Judd LL, et al. Am J Psychiatry. 2000;157:1501-1504. 8.de Groot M, et al. Psychosom Med. 2001;63:619-630. 2.Paykel ES, et al. Psychol Med. 1995;25:1171-1180. 9.Frasure-Smith N, et al. JAMA. 1993;270:1819-1825. 3.Thase ME, et al. Am J Psychiatry. 1992;149:1046-1052. 10.Penninx BWJH, et al. Arch Gen Psychiatry. 2001;58:221-227. 4.Miller IW, et al. J Clin Psychiatry. 1998;59:608-619. 11.Vaccarino V, et al. J Am Coll Cardiol. 2001;38:199-205. 5.Murphy27/05/17 JM, et al. Arch Gen Psychiatry. 1987;44:473-480. 12.Ickovics JR, et al. JAMA. 2001;285:1466-1474. 6.Everson SA, et al. Arch Intern Med. 1998;158:1133-1138. 13.Judd LL, et al. J Affect Disord. 1997;45:5-18 7.Lustman PJ, et al. Diabetes Care. 2000;23:934-942. 14 Fekadu A et al . J Affect Disord 2016 pp4-11 Depression & Neuro-anatomic Changes

• Evidence of correlation between neuro-anatomic changes and disease is rapidly expanding1-7: – Hippocampal volume reduced in major depression – Changes greater with chronic or recurrent disease – Volume changes may persist after resolution – Changes either precede illness onset or originate with chronic illness

4. Mervaala E, et al. Psychol Med. 2000;30:117-125. 1. Sheline YI,27/05/17 et al. Proc Natl Acad Sci USA. 1996;93:3908-3913. 5. Steffens DC, et al. Biol Psychiatry. 2000;48:301-309. 2. Sheline YI, et al. J Neurosci. 1999;19:5034-5043. 6. Frodl T, et al. Am J Psychiatry. 2002;159:1112-1118. 3. Bremner JD, et al. Am J Psychiatry. 2000;157:115-118. 7. Sheline YI, et al. Am J Psychiatry. 2003;160:1516-1518. Decreased Activity in DLPFC and dACC in Patients With MDD

• Areas of increased activation in patients with MDD at rest red and decreased activation blue compared with controls • Increased activity: LOPFC, VMPFC, amygdala, thalamus, caudate nucleus • Decreased activity: DLPFC, insula, pregenual and dACC, superior temporal gyrus dACC=Dorsal anterior cingulate cortex; DLPFC=Dorsolateral prefrontal cortex; LOPFC=Lateral orbital prefrontal cortex; MDD=Major depressive disorder; VMPFC=Ventromedial prefrontal cortex. 27/05/17 Fitzgerald. Hum Brain Mapp 2008;29(6):683-95. Summary: Structural and Functional Changes in MDD

MDD=Major depressive disorder. 27/05/17 aan het Rot et al. CMAJ 2009;180(3):305-13. © Canadian Medical Association Journal. Can Treatment Prevent or Reverse the Damage?

Dendritic ?? STRESS branching Increased Atrophy/death Glucocorticoids survival and of neurons growth BDNF

BDNF Normal survival and Glucocorticoids growth 5-HT and NE

Pharmacotherapy, ECT, psychotherapy, rTMS exercise Sapolsky RM. Arch Gen Psychiatry. 2000;57:925-935. Duman RS, et al. Biol Psychiatry. 2000;48:732-739. 27/05/17 Management

27/05/17 Do antidepressants work?

Kirsch27/05/17 et al 2008 Plos Initial Severity and Antidepressant Benefits: A Meta- Analysis of Data Submitted to the Food and Drug Administration Cognitive Therapy and Medications Affect the Brain in Complementary Ways

ADM=Antidepressant medication; CT=Cognitive therapy; PFC=Prefrontal cortex. 27/05/17 DeRubeis et al. Nature Rev Neurosci 2008;9(10):788-96. Depression: overall treatment strategies • Remove or control contributing factors • Psycho-education re depression • Phase specific psychotherapy • Stress management/exercise • Targeted dosing of primary medication – Antidepressants if unipolar – Mood stabilisers if bipolar – Specialist care/combinations if high acuity

27/05/17 Treatment Strategies 2 • Psychosocial – Psychotherapy • Supportive & Structured problem solving • Interpersonal & Cognitive-behavioural therapy – Relaxation training – Structured time • some social stimulation • exercise • Antidepressants – SSRI’s – SNRI/NaSSA – TCA’s & heterocyclic AD

27/05/17– RIMA’s, MAOI’s Treatment Strategies 3 • Other Pharmacotherapy – Acute phase/severe anxiety • add benzodiazepines – Psychotic depression/severe melancholic depression • add antipsychotics – Bipolar depression - additional • atypical antipsychotics • lamotrigine • ECT – Rx of choice in psychotic depression or severe melancholic depression

27/05/17 Factors to Consider in Patients Failing First Trial of Antidepressant Monotherapy

Correct Diagnosis Comorbid psychiatric conditions Comorbid medical conditions

Appropriate drug Treatment- therapy refractory patient Adequate dose

Severity of Adequate duration illness compliance

27/05/17 Whats next?

Switch Augment/Combine • If no/partial response • If partial response • Preferably a different • Choose augmentation class based on subtype of • TCA or SNRI for depression or melancholia comorbidity • SSRI or AGM or – Psychotherapy NaSSA or MAOI if – AAP bipolar & mood – Lithium nd stabilised – 2 AD

27/05/17 Augmentation

Strategies Lithium/T3 Exercise Other e.g. Stimulants

CBT, IPT & mindfulness ECT & psychotherapy Primary AD other brain stimulation

Atypical 2nd AD Antipsychotic Mood Stabilizer 27/05/17 ECT for Depression

27/05/17 rTMS for Depression

27/05/17 tDCS for Depression

27/05/17 DBS for depression

27/05/17 Refractory depression

• Most refractory depression is due to either – inadequate biological treament of melancholic depression or – inadequate psychosocial treatment of non- melancholic depression

27/05/17 Melancholic Depression - Unipolar

• Psycho-education re depression as treatable brain illness • Optimise pharmacotherapy – Broad spectrum AD • SNRI, TCA (therapeutic serum monitoring), MAOI – Augment • Atypical antipsychotics – e.g. olanzapine 2.5-10mg • Lithium • Stimulant

• ? T3 – Combination AD • SNRI + NaSSA/AGM/Buproprion • SSRI + NaSSA/AGM/Buproprion • Specialised combinations TCA + SSRI, TCA + MAOI

27/05/17 Melancholic Depression - Bipolar

• Optimise pharmacotherapy starting with mood stabiliser – Lithium – Augment • Atypical antipsychotic– e.g. OLZ or QTP • Lamotrigine – Care with AD • SSRI • MAOI – ECT highly effective v medication – Other • Stimulant

• ? T3

27/05/17 Melancholic Depression

• Electro-Convulsive Therapy (ECT)1-5 • Rapid and increased rates of both response and remission • Modern approaches less acute confusion/memory disturbance • Older patients response rates >> than to medication • Bipolar patients response rates >> than to medication – Response • psychotic depression ≈ 90-94% (2/3 remit) • melancholia without psychosis ≈ 80% (2/3 remit) • drops to ≈ 50-60% if last line (chronicity likelihood of remission) – Maintenance ECT • Equivalent or better outcomes than pharmacotherapy alone

27/05/17 Melancholic depression with psychosis/agitation • High risk state psychiatric admission warranted • Electro-Convulsive Therapy (ECT) - equal 1st line as rapid, near certain response • Combination broad spectrum AD and AAP • SNRI (generous dose) or TCA (therapeutic levels) or MAOI AND • Atypical antipsychotics – e.g. olanzapine 2.5-10mg or risperidone 1-4 mg

27/05/17 Non-melancholic

• Remove / control contributing factors – stress management and conflict resolution • Psycho-educate – bio-psycho-social approach to a treatable illness – risk/vulnerability and relapse prevention – family/partner/carer education - a co-therapist • Psychotherapy1,2 – Several shown to work (tailor to specific needs) from IPT, CBT, DBT, family or marital therapy • Exercise/Lifestyle – mild to moderate depression – best evidence for resistance and HITS

27/05/17 1. Wiles et al, Lancet 2016 2. Trivedi R et al, J Gen Intern Med 2011 Non-melancholic depression • Pharmacotherapy – Tolerable modern AD aiming for target dose • SSRI/NaSSA/AGM/SNRI/Vor – Strategies if anxiety/distress ++ severe ++ disabling ++ • high dose AD /broad spectrum SNRI • augmentation lithium or atypical antipsychotics • combination AD • rTMS or ECT - non-melancholic approx 50-60% srill respond

27/05/17 Non-melancholic depression • Treat co-morbidity – Anxiety • Relaxation training/CBT/benzodiazepines • OCD Rx – ADHD • Stimulant/ATX • Psychology/Coaching – Substance use disorders • Treatment programs • SUD medications – Chronic pain • Stabilise analgesia/pregabalin (neuralgic) • Rehabilitation model • SNRI or TCA

27/05/17 Summary

• Depression typically a chronic relapsing disorder • Phased multimodal management based on diagnostic sub-type and illness severity • Non-melancholic depression – multiple treatment options – psychological work helpful – medication helpful but not essential • Melancholic depression – active medical management essential – psychological work phase dependent

27/05/17 Summary

• Goal usually remission as untreated depression has severe consequences • Rational poly-pharmacy is good medicine for severely depressed / complex cases • Brain stimulation options emerging, for now ECT – of profound acute benefit for melancholic patients – remains an option for intractable illnesses

27/05/17 Case Scenario 1

• 70 year old Japanese-Australian – Chronic depression • non-melancholic anxious/worrier – Chronic abdominal pain • opiate dependence in remission • pain specialist review – little to offer – Alcohol/sedative dependence • Partially controlled – Serious suicide attempts > 3 occasions – SSRI nonresponse, TCA nonresponsive – SNRI limited to < 225mg (5HT syndrome) – Ltd benefit from CBT/group DBT/fortnightly supportive psychotherapy

27/05/17 Case scenario 2

• 37 year old Anglo-Australian woman. Mother of two, part time work as nurse. – Bipolar disorder type II – severe MDE with melancholia and intense suicidality – Violent, controlling and critical father – Good marriage, finances OK, no substance use – 1st Episode postnatal responded to SSRI and psychotherapy – Now depressed failed SSRI at higher doses then TCA – dothiepin and valproate

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