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
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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
22/02/2012
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
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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
22/02/2012
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
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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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