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Presenter : Dr. Imon Paul
Chairperson : Dr. S K Chaturvedi
22/02/2012
OUTLINE Introduction Pharmacotherapy Emerging pharmacotherapies for MDD New directions Neurotherapeutics Vagal nerve stimulation Transcranial direct current stimulation Transcranial magnetic stimulation Magnetic seizure therapy Deep brain stimulation Epidural prefontal cortical stimulation22/02/2012 2
Psychological Interventions Newer therapies Recommendations in Depression Natural or Alternative therapies Indian Scenario Conclusion
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INTRODUCTION Depressive disorders, including major depression &
dysthymia, are serious disabling illnesses. Treatment aims at complete symptom remission,
complete restoration of day-to day function prevention of relapses and recurrences.
Numerous ADs & empirically documented, time-
limited psychotherapies available. Typically treated with medication, psychotherapy, or a combination of both.22/02/2012 4
Newer therapies for treatment of Depression What comprises newer therapies? What is the rationale behind their emergence? How safe and effective are these?
How are they different from existing therapies? How do they help us? Applicability and cost effectiveness? Use in special population?
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Is it possible to develop a new drug which requires
single dosage & acts instantaneously? Introduction of SSRIs led to a shift from psychiatrist clinic to GP- will newer therapies continue this trend? What are the implications in community psychiatry? Can surgery cure depression? Can therapy be possible in the convenience of ones home? Is a new AD vaccine in the offing?6
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PHARMACOTHERAPY
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Emerging pharmacotherapies for MDD Newer therapies have focused on limitations of existing
therapies
moderate efficacy relative to placebo relatively slow onset of action Unacceptable side effects possible withdrawal symptoms problems of compliance Rapid onset of action Intermediate Half Life Defined therapeutic blood level No side effects Minimal Drug Interactions Low toxicity with over dosage Broad spectrum of efficacy8
The ideal antidepressant
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Agomelatine Developed from concept of disturbed circadian rhythm in
depression Melatonergic receptor agonist (MT1/MT2) and 5HT2C antagonist favorable balance between efficacy & tolerability (no weight gain, no sexual dysfunctions) Active comparator trials show comparable efficacy with other ADs (PXT, venlafaxine, SRT, FXT) Efficacy demonstrated in severe depression and in treating anxiety symptoms associated with major depression and also in relapse preventionDemyttenaere K, 2011
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The Triple-Reuptake Premise Dopaminergic circuit dysfunction linked to depression mesocorticolimbic dopamine system involved in motivation, psychomotor speed concentration Ability to experience pleasure neurogenesis broad-spectrum AD will produce a more rapid onset &
better efficacy sexual dysfunction seen with SSRIs would be attenuated22/02/2012 10
Triple reuptake inhibitors Amitifadine is a serotonin-preferring triple reuptake
inhibitor relative potency to inhibit serotonin, norepinephrine, and dopamine uptake of ~1:2:8, respectively. initial clinical trial in patients with severe depression demonstrated significant AD activity including attenuating symptoms of anhedonia tolerability profile comparable to placebo.Tran et al., 2012
several compounds have entered clinical trials, such as DOV 216,303, DOV 21,947, NS-2359, and SEP-22528922/02/2012 11
Drugs Enhancing Dopaminergic System Pramipexole, - D2 agonist / 5-HT2 antagonist RCT compared pramipexole to FXT and placebo in 174
subjects with non-refractory unipolar MDD. At 8 weeks, pramipexole performed comparably to FXT & significantly better than placeboCorrigan et al., 2000
In a open-label, nonrandomized, prospective study,
pramipexole added to ADs was effective for improving stage 2 TRD in 6 of 10 patients based on the primary outcome (MADRS score)Inoue et al., 201022/02/2012 12
Emerging role for glutamate neurotransmission in search for pathogenesis of major depression. Novel approaches focused on intracellular targets that
regulate neuroplasticity & cell survival. Loss of synaptic plasticity & hippocampal atrophy genetic susceptibility & environmental factors make hippocampal neurons more vulnerable to stress. Stress-induced activation of glutamatergic transmission induces neuronal cell death through excessive stimulation of NMDA receptors. NMDA antagonists effective in animal models of depression and appear to be effective also in clinical trials13
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GLUTAMATE BASED ANTIDEPRESSANTSKetamine Noncompetitive NMDA glutamate receptor antagonist Single dose ketamine response shown to produce rapid & significant AD response compared to placebo in recent studies Rapid reduction in suicidal ideas reported in one studyBerman et al., 2000; Zarate et al., 2006
Memantine mixed results in depression Traxoprodil NR2B selective antagonist AD action compared to placebo but dissociative sx Larger sample sizes, long-term cognitive impairment of repeated infusions, treatment-related psychological side effects, use of active comparators, possible concomitant use with ADs need investigation22/02/2012 14
Aripiprazole Partial agonist at D2, partial agonist at 5-HT 1A &
antagonist at 5-HT2A. Adjunctive Arp may be useful in treatment of bipolar depression MDD TRD
future adequately-powered, well designed, placebocontrolled trials required to comment on efficacyPae et al., 200822/02/2012 15
Cortisol Synthesis Inhibition: A New Treatment Strategy overactivity of HPA axis causes overproduction of cortisol Antiglucocorticoids may have AD effects In a Cochrane review, 9 studies evaluated- mifepristone,
ketoconazole, metyrapone, and DHEA no significant difference in overall proportion of patients responding to antiglucocorticoids over placebo Of 5 trials in non-psychotic depression (unipolar or bipolar), there was a significant difference favouring treatment Results in some diagnostic subtypes are promising and warrant further investigationGallagher et al., 200822/02/2012 16
New Directions Neuropeptides Substance P antagonists Thyrotropin-releasing hormone Neuropeptide Y Vasopressin receptor antagonistsVetulani and Nalepa, 2000
Vilazodone - serotonin reuptake inhibitor & partial 5-HT1 Aagonist under clinical evaluation for the treatment of major depression awaiting approval by FDA Mixed results in phase II trials
Perovic et al., 201022/02/2012 17
Riluzole glutamate-modulating agent showed AD properties and was well tolerated role as mono/ adjunctive therapy remains to be establishedPerovic et al., 2010
5-HT1Aagonists- gepirone, buspirone reported to exert anxiolytic and antidepressive activity in double-blind, placebo-controlled, and comparative trials. Recognition of clinical efficacy hampered by their undesirable pharmacokinetic properties.Blier and Ward, 2003
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Summary
Relapse prevention- Agomelatine Less weight gain Agomelatine, Aripiprazole Less sexual side effects Agomelatine, Amitifadine Rapid onset of action- Ketamine Less frequent dosing- Ketamine Effective in anhedonia- Amitifadine Effective in bipolar depression- Aripiprazole Not effective in psychotic depression- Antiglucocorticoids Potential abuse liability- TRIs, Ketamine Possible rapid reduction in suicidal ideas- Ketamine Dissociative symptoms- Ketamine, Traxoprodil19
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Neurotherapeutics
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Vagus nerve stimulation Device implanted in Left chest wall Delivers electrical signal through an implanted lead
wrapped around left cervical vagus nv. V. nerve sends sensory information from periphery to brain LC raphe nuclei NTS.
induces changes in rCBF similar to changes seen with ADs FDA approval for TRD in July of 2005
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Efficacy In majority of open studies VNS showed significant
reduction of depressive symptoms in short & long term. Only 1 randomized study published - inconclusive results Further clinical trials are needed to confirm efficacyDaban et al., 2008
Rec. as adjunctive treatment for adults with a h/o recurrent or chronic depression who have failed at least 4 adequate antidepressant medication trialsMarangell et el., 2007
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Transcranial direct current stimulation tDCS - non-invasive brain stimulation
technique mild (12 mA) direct currents applied via scalp classed as anodal or cathodal Enhances/ diminishes neuronal excitability. neurons underlying the anode are excited neurons underlying the cathode are inhibited Can be used for investigating cortical function. Potential treatment for neuropsychiatric diseases, by modulating excitabilityArul-Anandam & Loo, 2009
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Study Redfearn et al., 1964
Design Pilot study applying anodal tDCS
N 29
Findings 13 showed clin improvement, 11 showed mild/improvement, and 5 dropped out no differences b/w active and sham conditions 14 showed definite improvement, 4equivocal and 2no improvement.
Arfai et al., 1970
Double-blinded 19 sham-controlled trial Open-label trial 20
Ramsay et al., 1966
Fregni et al., 2006
Double-blinded, sham controlled trial of anodal tDCSDouble-blinded, sham controlled trial comparing prefrontal, occipital and sham tDCS
10
4 out of 5 in active group responded, compared to no responders in sham groupSignificantly greater reductions in depression rating scores after DLPFC tDCS compared to occipital tDCS and sham tDCS. Beneficial effects in the DLPFC group persisted on one-month follow up.24
Boggio et al., 2008
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Transcranial magnetic stimulation rapidly alternating current passes through small coil
over scalp
generates a magnetic field that induces an electric field
in underlying areas of the brain
ionic currents are generated
neuronal depolarization occurs22/02/2012 25
Use in depression Patients with depression hypothesized to have
reduced activity in left PFC. Many rTMS studies were designed to excite this area with high frequency stimulation Recent hypothesis - imbalance in activity of frontal lobes, with hypofunction in the left frontal lobe caused by excessive inhibition from the right one.
alternative t/t would be low-frequency (suppressive) rTMS of right PFC 22/02/2012
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EFFICACY First meta-analyses on the efficacy of rTMS for depression
showed mixed results. Recent studies support antidepressant efficacy of rTMS esp. longer periods of stimulation (e.g. > 2 weeks). rTMS seems effective & safe as acute treatment Poor response in psychotic depression, elderly, longer duration of illness & treatment resistance Further studies needed to better define specific stimulationrelated issues, duration of treatment, durability of effects & predictors of response. FDA approval in 2008 for treatment of patients with medication-refractory unipolar depressionDellOsso et al., 201127
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Magnetic seizure therapy rTMS at higher doses & convulsive parameters purposefully induces therapeutic seizures under GA magnetically induced seizures compared to ECT more
spatially precise, less susceptible to surface tissue impedance and had greater control of intracerebral spatial distribution Equipment still in prototype stage potentially useful variant of ECTRosa and Lisanby, 2012
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DEEP BRAIN STIMULATION adjustable & reversible method of
focally modulating activity of dysfunctional brain circuits with electrical stimulation. Electrodes placed in specified brain regions Attached to subcut Power Generators on chest wall Aims to decrease metabolic hyperactivity in Subgenual cingulated region22/02/2012 29
Efficacy 20 patients with TRD underwent Subcallosal Cingulate
Gyrus DBS. 1 m after surgery, 35% showed response with 10% in remission. At 6 m, 60% were responders and 35% in remission Benefits maintained at 12 mLozano et al., 2008
10 pts. implanted with DBS electrodes in Nucleus Accumbens After 12 m, 5 reached 50% reduction of HDRS. No. of hedonic activities increased significantlyBewernick et al., 2010
DBS is still in early investigational state for all psychiatric indications including TRD22/02/2012 30
Epidural Prefrontal Cortical Stimulation Leads placed through a burr hole in the skull but
above dura mater In a recent study, 5 adults recruited 4 cortical stimulation paddle leads stereotactically placed over both anterior frontal poles and midlateral PFC. All patients tolerated therapy. At 7-m f/u, avg improvement from preimplant baseline on HRSD and Inventory of Depressive SymptomsSelfReport were 54.9% and 60.1% 3 implanted subjects reached remission.Nahas et al., 201031
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SUMMARY
Less invasive- rTMS, tDCS, MST More invasive- VNS, DBS, EpCS Cost- more for VNS, DBS Seizure risk- rTMS Can be used in acute phase rTMS Delayed onset of action- VNS Long term maintenance- VNS Cardiac risk- VNS Can be used in BPD- VNS Possible use in anhedonia- DBS (NAcc)32
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PSYCHOLOGICAL INTERVENTIONS
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NEWER THERAPIESCognitive-Behavioural Analysis System of Psychotherapy Developed specifically for chronic depression Focused on recognizing how maladaptive cognitions & behaviours influence each other & lead to & perpetuate negative outcomes. Negative relationship patterns seen as a particular difficulty Therapeutic relationship serves as medium for negative interpersonal behaviours to be changed Efficacy shown in chronic depression, double depression and RDDSwan and Hull, 200722/02/2012 34
Third Wave of CBT Cognitions and cognitive thought processes as a form
of private behaviour Targets emotional response to situation focus primarily on function of cognitions- thought suppression or experiential avoidance Strategies Mindfulness
Acceptance of unwanted thoughts and feelings Cognitive diffusion
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Acceptance and Commitment Therapy (ACT) Psychopathology results from experiential avoidance Aim to increase acceptance of full range of subjective
experiences, including distressing thoughts, beliefs, sensations & feelingsHayes, 2004
Cognitive defusion Acceptance Contact with the present moment Use of the observing self Personal values Committed action Further research requiredStirman et al., 201022/02/2012 36
COMPASSIONATE MIND TRAINING Motivate to care for own wellbeing to be sensitive to own needs and distress extend warmth & understanding towards themselves employ self-soothing actions along with CBT techniques, compassionate meditation and imageryGilbert, 2009
META-COGNITIVE THERAPY Depression maintained by problematic and difficult to control thinking patterns rumination and excessive self-focused attention on thoughts and feelings incorporates attention trainingWells, 200822/02/2012 37
Behavioural Activation
Compromised environmental sources of (+) reinforcement increasing activity & access to rewarding experiences Consequences of depressive vs non-depressive behaviour de-emphasizing particular cognitions or mood states as necessary for re-engaging with one's environment.Jacobson et al., 1996
Mindfulness-based cognitive therapy Manualised group-skills training programme to address
vulnerability b/w episodes of RDD MBCT had strongest preventive effects on patients with 3 or more prior episodes Not intended for acute therapyHollon and Ponniah, 201022/02/2012 38
Positive Psychotherapy Foster engagement, meaning & positive emotion. Refocus attention & memory to positive aspects Discussions of problems & symptoms minimized Adjunctive therapy 2 small pilot studies with encouraging resultsStirman et al., 2010
Self-System Therapy Chr. failure to attain personal goals disorder in motivation & goal pursuit improve self-regulation to attain personal goals 1 RCT, SST vs CT no significant difference in outcomeStirman et al., 201022/02/2012 39
Bibliotherapy Reading of self-help materials for psychological treatment self-paced more convenient less costly No stigma Low motivation and energy experienced by depressed
patients may compromise adherence. 2 meta analysis of RCTs using bibliotherapy mixed resultsParikh et al., 200922/02/2012 40
Recommendations for individual psychotherapies for acute MDDFirst-line treatments Cognitive-Behavioural Therapy [CBT; Level 1] Interpersonal Therapy [IPT; Level 1] Bibliotherapy [Level 1] Behavioural Activation [Level 2] Cognitive-Behavioural Analysis System of Psychotherapy [CBASP; Level 2] Acceptance and Commitment Therapy [ACT; Level 3] Motivational Interviewing [Level 4] Psychodynamic therapy [Level 2] Emotion-Focused Therapy [Level 2]
Second- line treatments
Third-line treatments
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Recommendations for individual psychotherapies for maintenance phase of MDDFirst-line treatments Second-line treatments CBT [Level 1] Behavioural Activation [Level 2] CBASP [Level 2] IPT [Level 2] MBCT [Level 2] None with evidence ACT Motivational Interviewing Psychodynamic therapy Emotion-Focused Therapy Bibliotherapy
Third-line treatments Insufficient evidence to make a recommendation
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Natural or alternative remedies
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St. Johns Wort Extract of the flower of Hypericum perforatum L used for t/t of depression for centuries Contains polycyclic phenols, hypericin & pseudohypericin,
hyperforin Hypericin decreases serotonin receptor density hyperforin proposed to have 5 HT, NE and ACh reuptake inhibition shown to be more effective than placebo & equal to lowdose TCAs in most controlled trials less impressive results against the SSRIs and placebo in the more recent studiesMischoulon, 2007
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S-ADENOSYL METHIONINE
synthesized from l-methionine through 1 carbon cycle metabolic pathway involves vitamins folate and B12 low SAMe levels found in CSF of depressed individuals higher plasma SAMe levels associated with improvement in depressive symptoms Maybe effective as monotherapy/ adjunct may accelerate effect of conventional ADs well tolerated More research needed to determine optimal doses head-to-head comparisons with newer ADs lacking Potential role of folateMischoulon, 200745
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Second-tier natural antidepressants Rhodiola rosea- can be helpful in asthenic or lethargic
depression, and may be combined with conventional ADs to alleviate some of their common s/e Chromium- beneficial effect on eating-related atypical symptoms of depression & may be valuable in atypical depression & SAD 5-Hydroxytryptophan (5-HTP) Inositol well-designed, larger controlled studies needed before substantive conclusions can be drawnIovieno et al., 201146
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Exercise for depression Adjunct to usual treatment. Cochrane review of 25 RCTs which compared exercise with either
no treatment / established treatment Exercise seems to improve depressive symptoms When only methodologically robust trials included, the effect sizes moderate and not statistically significant. Further research requiredMead et al., 2009
Yoga for depression Hatha yoga, comprises asanas (postures), pranayama (breathing exercises) and dhyana (meditation). Pilkington et al. (2005), reviewed 5 RCTs utilising different forms of yoga in mild to severe depression- potentially beneficial effects of yoga reported but trials were not methodologically robust22/02/2012 47
SPIRITUALITY AND DEPRESSION relationship between religiosity & mental health -
perennial source of controversy Review of 850 studies by Moreira- Almeida et al.,2006 higher levels of religious involvement are positively associated
with indicators of psychological well-being (life satisfaction, happiness, positive affect, and higher morale) less depression, suicidal thoughts and behavior, drug/alcohol use/abuse positive impact of religious involvement on mental health is more robust among people under stressful circumstances (the elderly, and those with disability and medical illness)22/02/2012 48
INDIAN SCENARIORecent studies from India have focused on Utility of rTMS (left dorsolateral PFC) as an augmenting agent in TRD - Jhanwar et al., 2011 Ketamine in TRD Rao and Andrade , 2010 New views on the mechanism of action of ADsneuroplasticity as eventual mediator of AD efficacyAndrade and Rao, 2010
AD action of tramadol in animal studies- Kalra et al., 2008 Magnetic Resonance Spectroscopy in Depression with potential
implications in predicting response to treatmentRao et al., 201122/02/2012 49
CONCLUSION For newer somatic/ pharmacotherapies, long term
safety/efficacy data unknown new psychotherapies introduced & established in past 5 years have been different assimilations of previously established cognitive-behavioural or interpersonal models initial results are promising for some Study of these newer therapies may also help us understand pathoph ysiology of depression better No, an Antidepressant vaccine has not yet been discovered !!!22/02/2012 50
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