Resistance is not futile: working with refractory depression and anxiety

Transcription

1 Resistance is not futile: working with refractory depression and anxiety

2 Divulgation des conflits d intérêts Conseil consultatif ou comité analogue Essais cliniques ou études Honoraires ou autres revenus Valeant, BMS, Otsuka, Eli Lilly, Lundbeck, Janssen, Shire Subventions de recherche

3 Objectives: Define risk and evaluation factors in psychiatric resistance Review the canadian guidelines (CANMAT) in pharmacologically dealing with treatment resistance To know which modalities of intervention are more effective Review the new modalities, some controversial, in dealing with refractory illness Review the risk/benefit factors in augmentation and switching strategies

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5 How common is treatment resistant depression (trd)? Corey-Lisle and colleagues reported that approximately 22% of patients who received treatment for depression by their primary-care physicians remitted following 6 months of treatment, 32% were responders, while 45% were nonresponders University and speciality clinic studies not much better, listing resistance at 50% or more. Longer term follow up is slightly more positive

6 Achieving remission: Evidence of phyisiological resistance 50 Percent remission remission rate % Time after start of episode (months)

7 The price of resistance: Depressives smoke at 3 times the popn rate; even when well they have greater difficulty quitting Chronic depression doubles the risk of a heart attack and, if it persists, increases the short term mortality by 5 times Depression is the biggest risk factor for angina and death shortly after heart attack 87% of diagnosed breast cancer patients had severe depressive and anxiety symptoms in the 2 years prior

8 Further evidence; Treated depressives spend 59% of the next decades in a state of low grade depression By 3 rd episode of depression, relapse rate exceeds 90% 4 11/22/17

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10 The natural progression of depression: evidence for biologica resistance Major depression lifetime prevalance: 17% Dysthymia: 8% DSM low grade symptoms:25% response rate: 50-70% once treated: 25-35% remission continue residual illness: >50% risk of recurrence with residua: 5 times normal rate only 25% risk if patient put into remission 11/22/17

11 How to short circuit depression resistance Apply scales, labs, and good history to rule out other treatable co-morbidity: Borderline personality +/- dependent, narcissistic Workplace and adjustment dynamics: work role, stress, strain, interpersonal, secondary gain Hypothyroidism and metabolic imbalances, sleep apnea Bipolar depression: see criteria Comorbid anxiety +/- insomnia: careful use of benzos Substance overuse or abuse: even low grade alcohol, THC, hard drugs, benzos Do not wait: start pharmacotherapy +/- atypicals and go to next steps quickly: Rapid dose optimization with new generation drugs: easily dosed, effective, minimal SFX Knowledge of effective boosting strategies and their doses Use scale score guided depression treatment (PHQ ( and others) Optimize cognition quickly Weight gain early: switch; check for sleep, anxiety, sexual side effects: antidotes Comorbid atypical boosters: vitamins, light therapy, ketamine(?) Use adjunctive behavioral and cognitive strategies from the start, even if book or internet based: Behavioral activation framework Antidepressant skills workbook: slant towards employment and staying employed Exercise daily Whole foods diet/ Mediterranean: Viva L Italia!!!

12 How to short circuit depression resistance Apply scales, labs, and good history to rule out other treatable comorbidity: Borderline personality +/- dependent, narcissistic Workplace and adjustment dynamics: work role, stress, strain, interpersonal, secondary gain Hypothyroidism and metabolic imbalances, sleep apnea Bipolar depression: see criteria Comorbid anxiety +/- insomnia: careful use of benzos Substance overuse or abuse: even low grade alcohol, THC, hard drugs, benzos

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16 How to short circuit depression resistance Do not wait: start pharmacotherapy +/- atypicals and go to next steps quickly: Rapid dose optimization with new generation drugs: easily dosed, effective, minimal SFX crucial role of asthenia, sexual dysfunction Knowledge of effective boosting strategies and their doses Use scale score guided depression treatment (PHQ ( and others) Optimize cognition quickly Weight gain early: switch; check for sleep, anxiety, sexual side effects: antidotes Comorbid atypical boosters: vitamins, light therapy, ketamine(?)

17 MAX DOSE

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19 Antidepressants With Evidence for Superior Efficacy Based on Meta-Analyses Level 1 Antidepressant Escitalopram Comparators Citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine Mirtazapine Sertraline Venlafaxine Duloxetine, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine Duloxetine, fluoxetine, fluvoxamine, paroxetine Duloxetine, fluoxetine, fluvoxamine, paroxetine Level 2 Antidepressant Agomelatine Citalopram Comparators Fluoxetine, sertraline Paroxetine Return to algorithm SECTION 3 - Pharmacological Treatments Kennedy SH et al. Can J Psychiatry 2016;61(9):540-60

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22 Modern Antidepressants: What u really don t want: The Culprits: More Culprits: Lethality in overdose Tricyclics, effexor, wellbutrin, celexa (generally rare) Sexual side effects All cause except Trintellix, Wellbutrin, Remeron Blood pressure changes Effexor, wellbutrin, fetzima Metabolic/weight gain Paxil, Remeron Withdrawal syndrome (often severe) Effexor, Paxil, Pristiq, Cymbalta Worsening Anxiety Wellbutrin, prozac, fetzima Huge dosage ranges Effexor, zoloft Medication interactions Prozac, paxil, luvox Headache Celexa, prozac Oversedation Paxil, remeron, luvox

23 Modern Antidepresssants: What you want

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28 Newly Approved Antidepressants Antidepressant Mode of action Acute efficacy Maintenance therapy Vortioxetine Multimodal: Ø SRI Ø 5-HT 1A agonist Ø 5-HT 1B partial agonist Ø Antagonist at 5-HT 1D, 5-HT 3A, 5- HT 7 Meta-analysis of 12 RCTs was superior to PBO for response, remission Positive effects on multiple cognitive domains in MDD Superior to PBO for relapse prevention Vilazodone Multimodal: Ø SRI Ø 5-HT 1A partial agonist 12 RCTs 5 early trials failed 4 Phase 3 or 4 studies positive for 20 and 40 mg vs PBO None available Levomilnacipran SNRI Pooled analysis of 5 PBO-controlled RCTs was positive for response, remission No significant difference vs PBO for relapse prevention RCT, randomized controlled trial; SNRI, serotonin-noradrenaline reuptake inhibitor; SRI, serotonin reuptake inhibitor; PBO, placebo; MDD, major depressive disorder; GI, gastrointestinal SECTION 3 - Pharmacological Treatments Lam RW et al. Can J Psychiatry 2016;61(9):506-9

29 Adjuncts: General Considerations High doses of the adjunct often (Lithium) The response is seldom miraculously fast: 2-3 week trials needed; but atypicals often act in one week There will be side effects: tremor, weight gain, sexual dysfunction Adjuncts used too late, after biological resistance has crystallized Cost and compliance are issues Modern meds dosed correctly and quickly is a good start

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32 Adjunctive Strategies for Non or Partial Response 1 st LINE Aripiprazole (2-15 mg) Quetiapine ( mg) Risperidone (1-3 mg) 2 nd LINE Brexpiprazole* (1-3 mg) Olanzapine ( mg) Bupropion ( mg) Lithium ( mg [therapeutic serum levels]) Mirtazapine/mianserin (30-60 mg) Modafinil ( mg) Triiodothyronine (25-50 mcg) 3 rd LINE TCAs (e.g. desipramine) (various) Other antidepressants (various) Other stimulants (methylphenidate, lisdexamfetamine, etc) Ziprasidone (20-80 mg bid) *Newly approved since the 2009 CANMAT guidelines. TCA, tricyclic antidepressant; IV, intravenous; N/A, not applicable Return to algorithm SECTION 3 - Pharmacological Treatments Kennedy SH et al. Can J Psychiatry 2016;61(9):540-60

33 Preferential augmentation strategies Atypical antipsychotics Greatest knowledge base and effect sizes Low doses needed, except for Seroquel (at or greater than 150 mg po qhs) Metabolic/neurological side effects more marked in a depressed versus schizophrenic population Lithium Works as booster for all classes of antidepressant Rule out bipolarity if it does work! Doses needed: high; knowledge base: good Weight gain, renal monitoring, polyuria cognitive effects Combination antidepressants Do not start from beginning of therapy Use drugs with different mechanisms of action Proven inferior to the other 2 booster categories listed here

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39 What not to regularly use: St John s wart (sorry, wort) Liver toxicity, interactions, phototoxicity Kava Potentially addictive, hepatotoxicity Omega 3 oils Large number of pills: dyspepsia, fish smell, medication interactions Effect size?

40 MDD criteria: mood, physical, and cognitive symptoms 2 weeks in which a person has 5 symptoms that must include: Depressed mood and/or Loss of interest or pleasure plus 4 of: Significant changes in weight and/or appetite Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness or excessive/inappropriate guilt Diminished ability to think or concentrate, or indecisiveness Recurring thoughts of death or suicide, including plans and attempts DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th ed. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed

41 MDD is a multidimensional disease

42 Cognitive Impact of MDD Cognitive deficits are associated with significant impact on daily functioning and quality of life Cognitive dysfunction Is more strongly associated with loss of workplace productivity than ratings of depression severity Is a common symptom that can persist even after mood symptoms have remitted Clinical assessment and monitoring of cognitive symptoms during management of MDD is critical MDD, major depressive disorder SECTION 1 Principles of Care Lam R., et al., Can J Psychiatry 2016;61(9):

43 FDA Panel Backs Vortioxetine for Cognitive Dysfunction in MDD The US Food and Drug Administration's (FDA's) Psychopharmacologic Drug Advisory Committee has determined that there is substantial evidence to support claims that vortioxetine (Brintellix) is effective in the treatment of cognitive dysfunction in patients with major depressive disorder (MDD). The prevalence of cognitive dysfunction associated with depression is high, according to background information in the press release. In a 3-year prospective study of people treated for depression, cognitive symptoms (defined as diminished ability to think or concentrate and/or indecisiveness) was reported 94% of the time during acute major depressive episodes and 44% of the time during remission. Only vortioxetine shown to increase functionality in a series of objective measures of cognitive function.

44 The role of ECT Currently severely underused 75-80% effective in resistance where there is no severe personality disorder comorbidly if ect maintenance not continued past the initial remission period, 50% relapse rate in the next 2-3 years with antidepressants alone 93% maintenance rate if ect chronically administrated

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52 Ketamine improves suicidal thoughts in depression Wilkinson ST, et al. Am J Psychiatry. October 5, 2017 Meta-analysis results indicated a single dose of ketamine significantly and quickly improved suicidal ideation. To assess efficacy of a single dose of IV ketamine for suicidal ideation, researchers conducted a systematic review and individual participant data meta-analysis Studies used either saline or midazolam as a control treatment. At baseline, participants had a mean Montgomery-Åsberg Depression Rating Scale (MADRS) score of Analysis showed that within 1 day, ketamine significantly reduced suicidal ideation Effect sizes were moderate to large at all time points after dosing, according to results. Ketamine s effect on suicidal ideation remained significant when adjusting for concurrent changes in depression symptom severity.

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59 Patterns of marijuana use among psychiatry patients with depression and its impact on recovery. J Affect Disord. March 2017;312: Six-month recovery trajectories showed that marijuana use was significantly associated with worse recovery for depression symptoms (P = <.001) and anxiety symptoms (P =.025), and mental health functioning (P =.010) compared with patients not using marijuana. No significant differences in symptoms or mental health functioning outcomes (P's >.05) were found between patients who reported recreational or medicinal marijuana use Other research: Association between cannabis use (particularly frequent use) and the development of psychoses, including schizophrenia (substantial evidence). Increased suicidality and symptoms in Bipolar disorder.

60 How to short circuit depression resistance Use adjunctive behavioral and cognitive strategies from the start, even if book or internet based: Behavioral activation framework Antidepressant skills workbook (free online resource): slant towards employment and staying employed Exercise daily Whole foods diet/ Mediterranean: Viva L Italia!!! Keep abreast of employment-work friends, developments, relationships

61 Psychological Treatments for Acute Treatment of MDD Recommendation 1 st LINE 1 st LINE 1 st LINE 2 nd LINE 2 nd LINE 2 nd LINE 2 nd LINE 2 nd LINE 2 nd LINE 3 rd LINE 3 rd LINE 3 rd LINE 3 rd LINE Psychological Treatment Level of Evidence Cognitive-behavioural therapy (CBT) 1 Interpersonal therapy (IPT) 1 Behavioural activation (BA) 1 Mindfulness-based cognitive therapy (MBCT) 2 Cognitive-behavioural analysis system of psychotherapy (CBASP) 2 Problem-solving therapy (PST) 2 Short-term psychodynamic psychotherapy (STPP) 2 Telephone-delivered CBT, IPT 2 Internet- and computer-assisted therapy 2 Long-term psychodynamic psychotherapy (PDT) 3 Acceptance and commitment therapy (ACT) 3 Videoconferenced psychotherapy 3 Motivational interviewing (MI) 4 SECTION 2 - Psychological Treatments Parikh, S., et al., Can J Psychiatry 2016;61(9):524-39

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65 Preventing resistance:

66 Basics of avoiding or dealing with resistance Compliance measurement or repeated questioning (25% of resistant depression due to this) Comorbid drugs, THC, alcohol use: even 2-3 drinks/weekly can create resistance Comprehensive labs: including iron studies, testosterone, a.m. cortisol, ferritin, transferrin binding, thyroid studies, and the regular culprits Rule out bipolar illness Rule out borderline, dependent, and narcissistic personalities Role of stress, work problems, secondary gain Comorbid diagnoses, especially generalized anxiety disorder The use of low dose benzos and/or sleep agents temporarily early on appears to effectively combat much resistance and aid compliance Vital role for atypicals as augmentation strategies