Presentation on recent advances in dementia, classification in Psychiatry and depression

1. RECENT
ADVANCES IN
PSYCHIATRY
AMIT CHOUGULE MD, DPM

2. Why Study Recent Advances?
1. Theory exams (Paper – 4)
2. Practical exam (viva)
3. To be an up to date and optimistic clinician

3. RECENT ADVANCES-TEMPLATE
1.Advances in understanding/
Neurobiology
Genetics
Neural-Circuits
2.Advances in classification/ Nosology
3. Advances in diagnosis
f-MRI
PET/ SPECT
Genetic Markers
4.Advances in biological treatment
 New drugs
 New drug delivery systems
 Non invasive brain stimulation
5.Advances in Psychosocial treatment
 Newer psychological therapies
 Latest approach to rehabilitation
6. Advances in forensic or medico-legal
aspects

4. Template For Recent Advances
Past Advances
Neurobiology Chemical imbalance
Psychological
Dysfunctional Neural circuits
Biological
Brain imaging CT Brain, MRI Brain
Structural brain imaging
F-MRI, PET/SPECT, (MEG)
Functional Brain imaging
Genetics Family studies
Adoption studies
Twin studies
Linkage analysis
Genome wide association studies
Human genome project
Brain stimulation Electricity- ECT Magnetic- TMS, MST,
Invasive- DBS
Drug delivery Oral Depot, Implants, digital pills
Psycho-social
factors
CBT, REBT
Asylum, custodial care
Stigma, Abuse, Coercion
ACT, Mindfulness, Metacognitive therapy, AI
Day care centres, Community care
Legal protection, Advance directives

5. Dementia
 Advances In Nosology
 Advances In Prevention
 Advances In Understanding/
Neurobiology
 Advances In Diagnosis
 Advances In Treatment

6. DEMENTIA- ADVANCES IN NOSOLOGY
Criteria for AD since last three decades:
 No specific diagnosis is available until the dementia stage
 The diagnosis must be established in two steps:
1. Dementia syndrome
2. The underlying disease
 The dementia syndrome relied heavily on memory impairment
 AD was a diagnosis of exclusion, established when dementia is not due
to other brain pathologies

7. DEMENTIA-ADVANCES IN NOSOLOGY
 In DSM-5:
1. ‘Dementia’ is replaced by ‘Major Neuro-Cognitive Disorder (NCD)’
2. New category of less severe cognitive impairment ‘Mild NCD’
3. Memory impairment is no longer the main focus
4. Use of objective neurocognitive assessment
5. Better specification of behavioral symptoms and syndromes
6. Emerging role of biomarkers in future criteria
7. An updated listing of neurocognitive domains
(learning and memory, complex attention, executive function, perceptual-
motor abilities, social cognition, and language)

8. DEMENTIA- ADVANCES IN NOSOLOGY
DSM IV DSM 5
Individual criteria sets were designated for
dementia of the Alzheimer’s type and
vascular dementia
In DSM-5, major or mild vascular NCD and
major or mild NCD due to Alzheimer’s
disease have been retained
Other neurodegenerative disorders were
classified as:
Dementia due to another medical condition
(HIV, head trauma, Parkinson’s disease,
Huntington’s disease, Pick’s disease,
Creutzfeldt-Jakob disease, and other
conditions specified)
New separate criteria for major or mild
due to:
 Frontotemporal NCD
 Lewy bodies
 Traumatic brain injury
 Parkinson’s disease
 HIV infection
 Huntington’s disease
 Prion disease

9. ADVANCES IN PREVENTION OF DEMENTIA
 Confusion regarding the conceptualization of ‘disease’ in recent diagnostic
criteria
 Does AD start with the onset of specific pathological changes in the brain or does
it start with the first appearance of specific clinical symptoms ?
 Many elderly individuals die with intact cognition but have a AD-related
pathological signs in their brain

10. RECENT DEMENTIA PREVENTION STUDIES AND
INITIATIVES
 Several dementia prevention trials have been launched:
1. Targeting different populations
2. Using different types of lifestyle-related interventions
3. Pharmacological interventions
 New studies focus on multiple risk factors simultaneously
(multidomain interventions)

11. RECENT DEMENTIA PREVENTION STUDIES AND
INITIATIVES
 European Dementia Prevention Initiative: (EDPI)
 Cooperated from three ongoing prevention RCTs using multidomain
vascular and lifestyle-related interventions:
1. preDIVA (Prevention of dementia by intensive vascular care)
2. FINGER (The Finnish Geriatric Intervention Study to Prevent
Cognitive Impairment and Disability)
3. MAPT ((MultiDomain Alzheimer Preventive Trial)
 The Healthy Aging Through Internet Counselling in the Elderly
(HATICE)

12. RECENT DEMENTIA PREVENTION STUDIES AND
INITIATIVES
1. The PREVENT-Alzheimer programme
 Douglas Institute, Montreal, Canada
 500 individuals aged ≥55 years
 Without cognitive impairment but with a family history of AD
2. Promotion of the Mind Through Exercise (PROMoTE)
 University of British Columbia, Canada
 Targeting 70 participants aged ≥45 years
 With ischaemic vascular cognitive impairment
3. The Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing
(AIBL)
 50 individuals ≥60 years old
 With subjective memory complaints or MCI
 At least one cardiovascular risk factor

13. NEWER PATHOPHYSIOLOGICAL MECHANISMS IN AD
1. Inflammation [griffin, 2006]
2. Oxidative damage [reddy et al. 2009]
3. Iron deregulation [adlard and bush, 2006]
4. Cholesterol metabolism [Stefani and Liguri, 2009]
5. Impaired Insulin signalling in neuronal tissues

14. DEMENTIA-ADVANCES IN GENETICS
 1990 to 2000: Linkage Analysis
 3 genes for Familial Alzheimer's dementia (FAD): 5% cases
1. APP
2. PSEN-1
3. PSEN-2
 An extra copy of the APP gene in trisomy 21 leads to development of
AD pathology in Down syndrome
 Late onset Alzheimer's dementia: 95% cases
1. Complex inheritance
2. Do not follow Mendilian inheritance

15. DEMENTIA-ADVANCES IN GENETICS
APOE Gene and AD:
 Apolipoprotein E has three common isoforms, ε2, ε3 and ε4
 High avidity binding of Aβ to APOE
 Locus on chromosome 19
 APOE (ε3ε4) heterozygotes have a two to three fold higher risk of developing
AD compared to ε3ε3 homozygotes
 The increase in risk for ε4ε4 homozygotes is more than twice that of the ε3ε4
heterozygotes
 ε2 heterozygotes have a reduced risk

16. DEMENTIA-ADVANCES IN GENETICS
Genome Wide Association Studies (GWAS):
 GWAS has identified and confirmed new genetic risk factors for late
onset AD
 Allele C in the clusterin (CLU) gene
 Variants of AD-related genes such as PICALM, CR1, BIN1 have been
associated with AD-relevant measures such as:
1. Hippocampal volume or gray matter density
2. Entorhinal cortex thickness

17. DEMENTIA- ADVANCES IN DIAGNOSIS
Structural Brain Imaging:
MRI:
Automated
Software
Harvard’s
Freesurfer
Manual
Hippo-
campal
Volumetry
Qualitative visual
assessment
New Methods:
1. Tensor-based Morphometry (TBM):
• Correlation between rates of brain atrophy and rates of cognitive decline
2. Diffusion tensor imaging (DTI): to differentiate AD from FTD and DLB

19. DEMENTIA-ADVANCES IN DIAGNOSIS
Functional Neuroimaging
PET:
 Ability to utilize targeted radiotracers towards beta-amyloid
 To develop early neuroimaging biomarkers
 Pittsburgh Compound-B (PiB):
1. PiB helps to visualize Aβ ante mortem
2. PiB is a radioactive analog of thioflavin T
3. Investigate the role of Aβ in the process leading to AD
 Two new PET AB-binding agents have been developed:
1. Flutemetamol
2. Florbetapir (FDA approved for clinical use in April 2012)

22. ADVANCES IN DIAGNOSIS
FDG-PET:
 Decreased FDG uptake is an indicator of impaired synaptic function
 Both MCI and mildly affected AD subjects show a decrease in FDG
uptake in comparison to controls
 Early diagnosis of transition from MCI to AD

24. CSF studies in AD:
1. Aß1-42 reduced
2. Tau increased
3. Tau/Aß ratio
increased >1
suggests AD

25. DEMENTIA-ADVANCES IN DIAGNOSIS
Metabolomics:
 Metabolome is an accurate biochemical profile of the organism in
health and disease
 Metabolomics detects disequilibrium in the metabolome
 It reflects genomic, transcriptomic and proteomic fluctuations
 Applications:
1. Identification of biomarkers for early AD diagnosis
2. Discover novel therapeutic targets
3. Monitor therapeutic response and disease progression
 Magnetic Resonance Spectroscopy (MRS) is used

26. DEMENTIA-ADVANCES IN TREATMENT
Namzaric: (US FDA Approved in 2015)
 Fixed dose combination of memantine and donepezil
 Treatment of moderate to severe dementia of the Alzheimer’s type
 In patients stabilized on memantine hydrochloride and donepezil
hydrochloride
 Namzaric is available in two dosage strengths:
1. 28/10 mg (memantine extended release/donepezil)
2. 14/10 mg (memantine extended release/donepezil) for patients
with severe renal impairment

27. DISEASE-MODIFYING TREATMENTS:
MODULATION OF AMYLOID DEPOSITION

28. DISEASE-MODIFYING TREATMENTS:
MODULATION OF TAU DEPOSITION
Interfering with tau deposition Interfering with tau
phosphorylation
Immunotherapy
Methylene blue:
phase II trial (+)
Tau kinase inhibitors
(lithium: phase I trial
(–) in AD
(+) in MCI )
Vaccination:
preclinical trials
+, encouraging results
–, disappointing results
AD, Alzheimer’s disease
MCI, mild cognitive impairment

29. DISEASE-MODIFYING TREATMENTS:
MODULATION OF INFLAMMATION AND OXIDATIVE DAMAGE
1.Anti-inflammatory drugs:
 Long-term use of NSAIDs protects against the development of AD
2. Molecules addressing oxidative damage:
 Potential antioxidants include:
1. Mitoquinone
2. Vitamin E
3. Ginkgo biloba
4. Natural polyphenols such as green tea, wine, blueberries and
curcumin,
5. ω3 fatty acids, folate, vitamin B6 and vitamin B12 supplementation
 No beneficial effect on the primary cognitive measure

30. DISEASE-MODIFYING TREATMENTS:
MODULATION OF INFLAMMATION AND OXIDATIVE DAMAGE
3. Tumor Necrosis Factor (TNF) Inhibitor:
 TNF is a gliotransmitters
 Perispinal administration of Etanercept (TNFI) provides
sustained improvement in cognitive function in AD
 Etanercept merits further study in RCTs [Griffin, 2008]

31. DISEASE-MODIFYING TREATMENTS:
ADDITIONAL APPROACHES
Modulation of cholesterol and vascular-related risk factors:
1. The Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study:
 Atorvastatin 80mg daily in mild to moderate AD
2. Cholesterol Lowering Agent to Slow Progression (CLASP) of AD:
 Simvastatin
3. Insulin Nasal Spray:
 40 IU of insulin detemir in patients with AD carrying the APOE-e4
gene
 Significantly higher memory scores as compared those who
the lower dosage or placebo

32. Advances in
Classification/
Nosology in
Psychiatry

33. CLASSIFICATION IN PSYCHIATRY
1. Categorical classification
 Diagnostic criteria are provided for each disorder
 They indicate if a clinical presentation either meets or does not meet
the definitional requirements for a particular disorder
2. Dimensional:
 Variation in symptomatology can be represented by a set of
dimensions
 E.g Blood pressure which is measured along a continuum from low to
high
3. Hybrid:
 Categorical for broad diagnostic group
 Dimensional for severity

34. ADVANCES IN CLASSIFICATION
Problems with previous classifications and reasons for failure to discover a
single biomarker in Psychiatric disorder:
1. DSM/ ICD Categories are man made constructs and not a “natural
kinds”
2. Very difficult to find genes or a neurocircuit for a man made disorder
3. DSM/ICD Categories are not phenotypes
4. Heterogeneity within diagnostic categories
5. Comorbidity among disorders

35. ADVANCES IN CLASSIFICATION- RDoc
 The NIMH-sponsored Research Domain Criteria (RDoC) project is
intended to establish (Insel & Cuthbert, 2009)
“A framework for creating research classifications, that reflect
functional dimensions, stemming from translational research, on
genes, circuits, and behavior”
 Aim of the NIMH 2008 strategic plan:
“To develop, for research purposes, new ways of classifying mental
disorders based on dimensions of observable behavior and
neurobiological measures”

36. ADVANCES IN CLASSIFICATION- RDoc
The goal of RDoC is:
1. To shift researchers from diagnostic category based recruitment in
research studies towards a recruitment based on dysregulated
neurobiological systems
2. To form a precision medicine in Psychiatry so that clinicians can tailor
treatments to optimize outcomes for individual patients

37. ADVANCES IN CLASSIFICATION- RDoc
 RDoC framework takes a bottom–up approach:
 Starts with neural circuits to understand behaviours
 Current research takes a top–down approach:
 Starts with symptoms/ behaviours to understand the
pathophysiology of mental illnesses

38. The RDoC matrix
 Five major domains of functioning
 Each containing multiple, more specific
constructs:
1. Negative Valence Systems domain:
 Fear
 Distress
 Aggression
2. Positive Valence Systems domain:
 Reward seeking
 Learning
 Habit formation constructs
3. Cognitive Systems domain:
 Attention
 Perception
 Working memory/executive function
 Long-term memory
 Cognitive control
4. Systems for Social Processes domain:
 Separation fear
 Facial expression regulation
 Behavioral inhibition
5. Arousal/Regulatory Systems domain:
 sleep and wakefulness

39. The RDoC matrix
 The RDoC initiative promotes the examination of each construct across
7 units of analyses:
1. Genes
2. Molecules
3. Cells
4. Circuits
5. Physiology
6. Behaviour
7. Self-reports

41. RECENT ADVANCES
IN DEPRESSION
 Advances In Genetics
 Advances In Molecular Studies
 Advances In Neuro-imaging And
Neurobiology
 Advances In Treatment Of Depression

42. DEPRESSION-ADVANCES IN GENETICS
 Polygenic inheritance
 Interactions between genetic variants and environmental exposures
 MDD is associated with polymorphisms in:
1. The glucocorticoid receptor gene NR3C1
2. Monoamine oxidase A gene (MOA-Gene)
3. The gene for glycogen synthase kinase-3β (GSK-3β)
4. Group-2 metabotropic glutamate receptor gene (GRM3)
5. Serotonin transporter gene (SLC6A4)

43. ADVANCES IN MOLECULAR STUDIES OF DEPRESSION
Genetic variants of peripheral hormone-type factors associated with MDD:
1. Neurotrophic factors and other growth factors:
 BDNF
 Vascular Endothelial Growth Factor (VEGF)
 Insulin-like Growth Factor-1(ILGF-1)
2. Proinflammatory cytokines:
 Interleukin-1β
 Interleukin-6 (IL-6)
 Tumour Necrosis Factor-α (TNF-a)
3. Impaired regulation of the hypothalamic-pituitary-adrenocortical (HPA)
axis

44. DEPRESSION-ADVANCES IN GENETICS
Pharmacogenetics:
 The study of how genetic variation influences response to drug
1. Efficacy (efficacy pharmacogenetics)
2. Tolerability (safety pharmacogenetics)
 The AIM is:
1. To discover genetic profiles that can be determined by simple genetic
tests
2. To predict how patients will respond to psychotropic treatments
3. To allow physicians to tailor medications to maximizes efficacy and
tolerability (Personalized medicine)

45. ADVANCES IN GENETICS OF DEPRESSION
 A meta-analysis showed two associations:
1. 5HTTLPR long allele:
 Increased response to SSRI
 Reduced side-effects to SSRIs
2. 5HTTLPR short allele:
 Increased paroxetine-induced adverse effects
 Decreased mirtazapine-induced adverse effects
*HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene
that codes for the serotonin transporter

46. ADVANCES IN GENETICS OF DEPRESSION
 Studies of candidate genes have emphasised associations between:
1. Glutamatergic genes (GRIK4) and citalopram response and
adverse effects
2. Met allele of the functional Val/Met polymorphism (rs6265) in
BDNF and SSRI response
3. BDNF SNPs and desipramine response

47. ADVANCES IN GENETICS OF DEPRESSION
Genome-wide association studies:
Effectiveness of antidepressants can be predicted by genes for:
1. Corticotrophin-releasing hormone receptor-1 (CRHR1)
2. CRH binding protein (CRHBP)
3. Uronyl-2 sulphotransferase
4. Interleukin-1

48. ADVANCES IN GENETICS OF DEPRESSION
 Predictors of antidepressant response:
1. Genetic variation in FKBP5:
 A protein that regulates cortisol binding to glucocorticoid receptor
2. Genetic variation in the (COMT) gene
 Predictors of antidepressant non-response:
 Genetic variants in TREK1:
 A potassium channel mediating SSRI mechanism of action

49. ADVANCES IN NEUROBIOLOGY AND NEUROIMAGING
OF DEPRESSION
 Neural systems important in understanding MDD:
1. Emotion processing:
 Amygdala, ventral striatum, medial prefrontal and anterior
cortex
 Modulated by serotonin
2. Emotional regulation:
 Lateral prefrontal cortical systems (eg, VLPFC, DLPFC)
 Modulated by serotonin
3. Reward seeking:
 Ventral striatum, interconnected OFC and medial PFC
 Modulated by dopamine

50. ADVANCES IN NEUROBIOLOGY AND NEUROIMAGING
OF DEPRESSION
 Abnormalities in neural connectivity/circuits MDD:
1. Effective connectivity:
 Activity in one region exerts effect over another region in the
brain
2. Abnormal-inverse effective connectivity:
 Medial prefrontal cortex amygdala
 Abnormally increased top-down regulation of amygdala by
medial prefrontal cortex
 Bias away from attendance to positive emotional stimuli

51. Advances in Neurobiology and Neuroimaging of
depression
A meta-analysis identified two neural systems of importance in MDD:
1. First neural system:
 Centred on the dorsolateral (PFC) and anterior cingulate cortex
 Reduced activity in the resting state
 Activity returns to normal with treatment
2. Second neural system:
 Centred on medial PFC and subcortical regions
 Hyperactive to emotional stimuli in the depressed state
 Returns to normal after antidepressant treatment

52. ADVANCES IN TREATMENT OF DEPRESSION
Advances in treatments fall into four major categories:
1. Medications that optimize the modulation of monoaminergic
neurotransmitters
2. Medications that target non-monoamine neurotransmitter
3. Devices that produce focal electrical brain stimulation
4. Newer psycho-social treatment modalities in depression

53. RECENT ADVANCES IN TREATMENT OF DEPRESSION
OPTIMIZING MONOAMINERGIC MODULATION
 Growing database implicating Dopamine dysfunction in the pathophysiology
of depression
 Novel treatments in this category include:
1. Triple reuptake inhibitors:
 Triple reuptake inhibitors block synaptic reuptake of 5- HT, NE, and DA
 Tesofensine
 Sibutramine
2. Dopamine agonists:
 DA D2/D3 receptor agonists include pramipexole and ropinirole

54. RECENT ADVANCES IN TREATMENT OF DEPRESSION
OPTIMIZING MONOAMINERGIC MODULATION
3. Atypical antipsychotic augmentation:
 Antidepressant effects via DA function modulation and 5HT1A
1. Aripiprazole
2. Risperidone
3. Quetiapine
4. Olanzapine

55. RECENT ADVANCES IN TREATMENT OF DEPRESSION
Novel Pharmacological Targets: Beyond Monoamines
1.Corticotropin-releasing factor (CRF)-1 receptor antagonists
 Inhibition of glucocorticoid function
 Decreased synthesis or receptor blockade of adrenal glucocorticoids
may have antidepressant effects
 Agents that interfere with cortisol synthesis:
1. Ketaconozale
2. Aminogluthemide
3. Metyrapone
2.Glucocorticoid 2 receptor antagonist:
 Mifepristone (RU486)

56. RECENT ADVANCES IN TREATMENT OF DEPRESSION
Novel Pharmacological Targets: Beyond Monoamines
3. Substance P (NK-1) antagonists:
 Stress leads to elevated CSF substance P concentrations
 Decreased serum levels are seen with an antidepressant response
 E.g. Aprepitant (MK-869), GR-205171
4. Melatonin receptor agonists:
 Agomelatine
 A melatonin receptors 1 and 2 agonist (also a 5HT2C receptor
 Antidepressant effects

57. RECENT ADVANCES IN TREATMENT OF DEPRESSION
Novel Pharmacological Targets: Beyond Monoamines
5. Melanocyte-inhibiting factor:
 A small peptide (Pro-Leu- Gly-NH2) located in the CNS
 Associated with acute antidepressant effects in an early study
 Nemifitide is a novel analog of melanocyte-inhibiting factor
 Administered via subcutaneous injection
6. Omega 3 fatty acids:
 Ethyl-eicosapentanoate (EPA)
 Docosahexanoic acid (DHA)

58. RECENT ADVANCES IN TREATMENT OF DEPRESSION
Novel Pharmacological Targets: Beyond Monoamines
7. Glutamatergic modulation:
 Glutamate receptor antagonists may have antidepressant properties
1. Amantadine
2. ketamine
3. Memantine:
 Evidence in comorbid MDD and alcohol dependence
4. Riluzole
5. Traxoprodil:
 Selective antagonist of the NR2B subunit of NMDA receptor

59. RECENT ADVANCES IN TREATMENT OF DEPRESSION
Focal Brain Stimulation
1. Vagus Nerve Stimulation: (VNS)
 VNS is FDA-approved for long-term adjunctive treatment for recurrent
or chronic depression not responding to four or more medications
2. tDCS: Trans Cranial Direct Current Stimulation
 Lateral PFC tDCS demonstrated greater antidepressant efficacy
compared to occipital tDCS (active control) and sham tDCS in a single
double-blind, randomized, controlled study

60. RECENT ADVANCES IN TREATMENT OF
DEPRESSION
Focal Brain Stimulation
3. rTMS: Repeated Trans cranial Magnetic Stimulation
 High-frequency rTMS over the left (DLPFC) at adequate doses for a
minimum of 10 sessions has statistically significant antidepressant
effects in treatment resistant depression
4. Magnetic seizure therapy: (MST)
 MST involves using an rTMS device to create a generalized seizure
 Antidepressant effects similar or equivalent to high-dose right
unilateral ECT

61. RECENT ADVANCES IN TREATMENT OF DEPRESSION
Focal Brain Stimulation
5. Deep brain stimulation:
 Produced by a subclavian
subcutaneous pulse generator that
connects to neuro-surgically
implanted electrodes that stimulate
focused region in the brain
DBS targets in depression:
1. Subgenual cingulate white
matter
2. The anterior limb of the internal
capsule
3. The habenula
4. Nucleus accumbens
5. Thalamic peduncle

62. RECENT ADVANCES IN TREATMENT OF DEPRESSION
Focal Brain Stimulation
6. Epidural Prefrontal Cortical Stimulation:
 Leads placed through a burr hole in the skull, above dura mater
 4 cortical stimulation paddle leads are stereotactically placed
over
1. Anterior frontal poles
2. Midlateral PFC

63. RECENT ADVANCES IN TREATMENT OF DEPRESSION
PSYCHOSOCIAL INTERVENTIONS
 Third wave of Psychological therapies:
1. Acceptance and Commitment Therapy (ACT)
2. Compassionate mind training
3. Meta-cognitive therapy
4. Behavioural activation
5. Mindfulness based cognitive therapy
6. Positive psychotherapy
7. Self-system therapy

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