Recent advances in the management of depression

1. RECENT ADVANCES IN THE
MANAGEMENT OF DEPRESSION
Dr. Rakesh Verma
1st Year Junior Resident
Department of Clinical Pharmacology & Therapeutics

2. CONTENTS
 Depression
 WHO estimation
 Geographical Distribution
 Pathophysiology of Depression
 Depression and COVID-19
 Predictors for COVID-19 suicides
 Mental Health Status of Health Professionals during COVID
 Recent Studies on Depression
 Management of Depression
 Recent advances
 Drugs under Trial for Depression
 Take Home Messages
 List of Abbreviations
 References

3. Depression
Persistent feelings of sadness and hopelessness
and lose interest in activities once enjoyed
Lancet Psychiatry 2019

4. WHO estimation

5. Geographical distribution
15.5%
6.2%

6. • WHO 2016 estimates that the crude suicide rate for
Nepal stands at 8.8 suicides per 100,000 populations.
• At the time of lockdown from 24 March to Jun 6,
2020,suicide rate has been increased by 20 percent as
over 1,200 cases of suicide throughout the country has
been reported.
• This illustrates almost 17 lives have been lost per day
due to suicide during the period of lockdown.

7. Pathophysiology of Depression
Biological Factors Environmental Factors
Psychological factors

8. Pathophysiology of Depression
 Monoamine Hypothesis
 Neurotrophic Hypothesis
 Neuroendocrine Hypothesis

9. DSM-5 criterion for diagnosis
Five or more symptoms during the 2-week period and at
least one of the symptoms should be either
(1) depressed mood or,
(2) loss of interest or pleasure.
(3) Significant weight loss or weight gain
(4) Slowing down of thought and physical movement
(5) Fatigue or loss of energy
(6) Feelings of worthlessness or excessive or
inappropriate guilt
(7) Diminished ability to think or concentrate, or
indecisiveness
(8) Recurrent suicidal ideation with/without specific plan,
or a suicide attempt.

10. Depression and Covid-19
• Impacts of the COVID-19 pandemic on mental health
Globalization and Health,2020

11. Depression and Covid-19

12. Predictors for COVID-19 suicides
Brai, Behav. Immunity,2020

13. Mental Health Status of Health
Professionals during COVID
• “WHO has warned that long after the pandemic COVID-19 has
been brought under control, healthcare providers will have to
deal with the diverse mental health issues afflicting populations
in different countries.”
• Clinician wellness involves a number of factors including stress
and burnout.
• Greater clinician stress may lead to higher rates of drug and
alcohol addiction, divorce, and suicide.

14. Dr. Lorna Breen,
Manhattan ER doctor
EMT John Mondello
Dr. Yelena Nepomnyashchaya,
Russian Critical Care doctor

15. Recent Studies on Depression
• A descriptive cross-sectional study conducted among 680 nursing
students enrolled in nine colleges affiliated to Purbanchal
university in Nepal (2018)
• Depression anxiety stress scale- 21 was used to assess the levels
of depression, anxiety and stress.
• Coping was measured using brief cope inventory.
• Majority of students ( n = 350) reported moderate to extremely
severe levels of stress, anxiety, and depression..
J Nepal Health Res Counc 2019 Jul-Sep;17(44): 325-30

16. Recent Studies on Depression
• A cross-sectional survey conducted using an electronic
questionnaire with a total of 354 participants recruited through
convenience sampling
• Depression, anxiety and stress were measured using Depression
Anxiety Stress Scale (DASS-21), a 21 self-reported questionnaire
• 25%, 28% and 11.6% of the participants with moderate to
severely depressed, anxious and stressed respectively.
International Journal of Social Psychiatry 2020

17. Management of Depression

18. Non-Pharmacological
management of Depression
• Group interpersonal therapy (IPT)
• Multi-component behavioural treatment
-Problem-solving Counseling
- Managing Stress
- Behavioral Activation
- Strengthening social supports.
• Cognitive Behavioral Therapy

19. Cognitive Behavioral Therapy

20. Pharmacological Management of
Depression
HISTORY
1950
• Discovery of Chlorpromazine
1958
• Imipramine benefitted selectively depressed
but not agitated psychotics.
1961
• Discovery of Amitriptyline.

21. History of antidepressants

22. History of antidepressants

23. Classification of Antidepressants
1. Tricyclic Antiderpressants (NE+5HT):
Amytriptyline, Imipramine, Clomipramine, Doxepin.
2. Selective Serotonin,Norepinehrine Reuptake Inhibitors
(SNRIs): Duloxetine, Venlafaxine, Milnacipran.
3. Predominantly NA reuptake inhibitors:
Desipramine, Nortriptyline, Amoxapine, Reboxetine.
4. Selective serotonin reuptake inhibitors(SSRIs):
Fluoxetine,Paroxetine, Dapoxetine, Sertaline, Citalopram,
Escitalopram
5. Atypical antiderpressants: Trazodone, Mianserin, Mirtazapine,
Bupropion, Tianeptine, Amineptine, Atomoxetine.
6. Reversible inhibitors of MAO(A): Moclobemide, Clorgyline.

24. Precautions for TCAs-
• Avoid use in:
-Elderly
-CVD
-Dementia.
-Suicidal
tendencies

25. Choosing an appropriate antidepressant
• For adolescents 12 years and older- Fluoxetine
• For children under 12 years- No antidepressants.
• For pregnant or breastfeeding women- No antidepressants

27. Recent Advances
• Vortioxetine
• SNDRIs
• Vilazodone
• ALKS 5461

28. Vortioxetine
• Functions as SMS with a
majority of activity geared
towards serotonin and 5-HT
receptors.
• Affects adrenergic receptor,
acetylcholine & histamine.
• U.S.FDA and Europe
approved for treatment of
MDD in adults in September
2013.

29. SNDRIs-
• Acts as a combined reuptake inhibitor of the monoamine neurotransmitters
serotonin, norepinephrine, and dopamine.
• Inhibits the serotonin transporter (SERT), norepinephrine transporter
(NET), and dopamine transporter (DAT), respectively.
• Approved drugs: Mazindol and Nefazodone

30. Vilazodone
• Acts as serotonin reuptake inhibitors.
• Approved by USFDA in 2011.
• Indication: Major Depressive Disorders.

31. ALKS 5461
• Buprenorphine/samidorphan combination.
• In August 2017, based on the third trial, Alkermes
announced the initiation of a rolling submission of a New
Drug Application for ALKS- 5461 to the USFDA.

32. Drug under trial for depression
• Ketamine
• Intranasal esketamine
• Buprenorphine
• ALKS 5461
• Brexpiprazole
• Cariprazine
• Glutamatergic agents
• Ziprasidone
• Psilocybin
• Minocycline
• Tocilizumab
• Sirukumab

33. Ketamine
• Acts primarily as a glutamatergic modulator, but also as a
partial agonist at dopamine D2 receptors and as a dopamine
reuptake inhibitor.
• A recent study in mice showed that a ketamine metabolite is
essential for its antidepressant effects .
• In 2006, a randomized controlled trial (RCT) demonstrated that
a single intravenous dose of ketamine produced a robust and
rapid antidepressant effect in persons with TRD.
Arch Gen Psychiatry. 2006; 63:856–864

34. Intranasal esketamine
• S-enantiomer of ketamine, which possesses a 3–4-fold higher
affinity for NMDA receptors and greater anesthetic potency
than the R-ketamine enantiomer (arketamine).
• The U.S. FDA approved Spravato (esketamine) nasal spray, in
conjunction with an oral antidepressant, for the treatment of
depression in adults who have treatment-resistant depression.
• A rapid (within 2 h) and robust antidepressant effect was
observed after a 40-min infusion of either 0.20 mg/kg or 0.40
mg/kg of esketamine as compared with placebo.
Biol Psychiatry. 2015; 173:816–826

35. Psilocybin
• Mushroom alkaloid, which is rapidly converted by the body to
psilocin, a partial agonist for several brain serotonergic
receptors, particularly 5HT2AR.
• Also known as “Magic Mushroom”.
• In open-label trial of adjunctive psilocybin with MDD who had
failed to respond to at least two courses of antidepressant
treatment of different class, the acute psychedelic effects
peaked 2–3 h after dosing and declined to negligible levels at
least 6 h after dosing. Depressive symptoms were markedly
reduced 1 week and 3 months after highdose treatment.
Lancet Psychiatry. 2016; 3:619– 627.
• Recently, FDA marks psilocybin for depression treatment.

36. Take Home Messages
• MDD is a complex psychiatric condition, with multiple
aetiological factors.
• The pathophysiology of depression is still evolving with
ongoing molecular, genetic and neuroimaging studies.
• Evidence from neurobiological studies indicates that
monoamine hypothesis of depression cannot fully
explain the causation of depression.

37. Take Home Messages
• Though there have been considerable advances in the
treatment of depression since TCAs were discovered in
the 1950’s, the current treatments are not fully
satisfactory for either patients or clinicians.
• Research evidence on several new pharmacological and
non-pharmacological interventions is still preliminary and
further studies are needed to prove their actual benefits.

38. List of Abbreviations
COVID- Coronavirus disease
WHO- World Health Organization
DSM-5- Diagnostic and Statistical Manual of Mental Disorders-
5th edition
GBD- Global Burden of disease
CVD- Cardiovascular Disease
NCD- Non Communicable Disease
EMT- Emergency Medical technician
MANOVA- Multivariate Analysis Of Variance
MDD- Major Depressive Disorder
TRD- Treatment Resistant Depression
SNDRI- Serotonin–Norepinephrine–Dopamine Reuptake Inhibitor

39. References
1. World Health Organization (WHO). Coronavirus disease (COVID-2019) situation
reports 2020. Accessed 4 July 2020.
2. Chalise A, Paudel S. Mental Health Concern during COVID-19 Pandemic in
Nepal. Europasian J Med Sci.2020;2(Covid-19 Special Issue):39-44
3. Nora Ranjitkar Manandhar, Rabi Shakya, Bimal Pandey, Pratik
Wagley.Depression among patients undergoing maintenance hemodialysis at a
tertiary care center, in Kathmandu, Nepal. Journal of Patan Academy of Health
Sciences. 2018Dec;5(2):4-11
4. AlzayyatA, Al-Gamal E. Correlates of Stress and Coping among Jordanian
Nursing Students during Clinical Practice in Psychiatric-Mental Health Course.
Stress and Health. 2016; 32(4): 304-312.
5. Wang et al. BMC Psychiatry (2019) 19:303
6. Martinengo et al. BMC Medicine (2019) 17:231
7. Barkur, G., & Vibha Kamath, G. B. (2020). Sentiment analysis of nationwide
lockdown due to COVID 19 outbreak: Evidence from India. Asian Journal of
Psychiatry, 51, 102089

40. References
8. Neto MLR, Almeida HG, Esmeraldo JDa, Nobre CB, Pinheiro WR, de Oliveira
CRT, da Costa Sousa I, Lima OMML, Lima NNR, Moreira MM. When health
professionals look death in the eye: the mental health of professionals who deal
daily with the 2019 coronavirus outbreak. Psychiatry Research 2020:112972
9. Cascella M, Rajnik M, Cuomo A, Dulebohn SC, DiNapoli R. Features, evaluation
and treatment coronavirus (COVID-19)
10. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. 4th ed. Washington: American Psychiatric Association, 1994.
11. Dutheil F, Aubert C, Pereira B et al. Suicide among physicians and health-care
workers: a systematic review and meta-analysis. PLoS One 2019;14:e0226361.
12. Zarate et al, Vortioxetine versus sertraline in metabolic control, distress and
depression in Mexican patients with type 2 diabetes Ann Transl Med. 2019 Nov;
7(22): 656.
13. López-López JA et al (2019). The process and deliveryof CBT for depression in
adults: a systematic review and network meta-analysis. Psychological Medicine
49, 1937–1947.