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Dep Seem Final
Dep Seem Final
Imon Paul
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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 stimulation
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INTRODUCTION
Depressive disorders, including major depression &
limited psychotherapies available. Typically treated with medication, psychotherapy, or a combination of both.
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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?
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PHARMACOTHERAPY
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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 efficacy
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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 prevention
Demyttenaere K, 2011
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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-225289
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subjects with non-refractory unipolar MDD. At 8 weeks, pramipexole performed comparably to FXT & significantly better than placebo
Corrigan et al., 2000
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., 2010
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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 trials
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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 investigation
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Aripiprazole
Partial agonist at D2, partial agonist at 5-HT 1A &
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 investigation
Gallagher et al., 2008
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New Directions
Neuropeptides Substance P antagonists Thyrotropin-releasing hormone Neuropeptide Y Vasopressin receptor antagonists
Vetulani and Nalepa, 2000
Riluzole glutamate-modulating agent showed AD properties and was well tolerated role as mono/ adjunctive therapy remains to be established
Perovic 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, Traxoprodil
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Neurotherapeutics
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wrapped around left cervical vagus nv. V. nerve sends sensory information from periphery to brain
LC raphe nuclei NTS.
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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 efficacy
Daban 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 trials
Marangell et el., 2007
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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 excitability
Arul-Anandam & Loo, 2009
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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.
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over scalp
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.
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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 depression
DellOsso et al., 2011
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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 ECT
Rosa and Lisanby, 2012
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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 region
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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 m
Lozano 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 significantly
Bewernick et al., 2010
DBS is still in early investigational state for all psychiatric indications including TRD
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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., 2010
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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)
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PSYCHOLOGICAL INTERVENTIONS
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NEWER THERAPIES
Cognitive-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 RDD
Swan and Hull, 2007
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of private behaviour Targets emotional response to situation focus primarily on function of cognitions- thought suppression or experiential avoidance Strategies
Mindfulness
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Cognitive defusion Acceptance Contact with the present moment Use of the observing self Personal values Committed action Further research required
Stirman et al., 2010
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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 imagery
Gilbert, 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 training
Wells, 2008
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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
vulnerability b/w episodes of RDD MBCT had strongest preventive effects on patients with 3 or more prior episodes Not intended for acute therapy
Hollon and Ponniah, 2010
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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 results
Stirman 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 outcome
Stirman et al., 2010
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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 results
Parikh et al., 2009
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Third-line treatments
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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 studies
Mischoulon, 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 folate
Mischoulon, 2007
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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 drawn
Iovieno et al., 2011
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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 required
Mead 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 robust
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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)
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INDIAN SCENARIO
Recent 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 efficacy
Andrade and Rao, 2010
AD action of tramadol in animal studies- Kalra et al., 2008 Magnetic Resonance Spectroscopy in Depression with potential
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 !!!
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