Kerangka Konsep

Judul: Biopharmaceutical Aspect of Major Depression Disorder

1. Background
• Major depression is defined as depressed mood on a daily basis for a minimum
duration of 2 weeks (Reus, 2015)
• Approximately 15% of the population experiences a major depressive episode at
some point in life. Approximately 4-5% of all depressed patients will commit
suicide; most will have sought help from physicians within 1 month of their deaths
(Reus, 2015).
• Based on Riset Kesehatan Dasar (Riskesdas) survey 2007, depression and anxiety
patient Indonesia approximately 11,60% or 24.708.000 of total population.
• Specific symptoms, at least 5 of these 9, present nearly every day (DSM-IV, 1994).:
1. Depressed mood or irritable most of the day, nearly every day, as indicated by
either subjective report (e.g., feels sad or empty) or observation made by others
(e.g., appears tearful).
2. Decreased interest or pleasure in most activities, most of each day
3. Significant weight change (5 %) or change in appetite
4. Change in sleep: Insomnia or hypersomnia
5. Change in activity: Psychomotor agitation or retardation
6. Fatigue or loss of energy
7. Guilt/worthlessness:Feelings of worthlessness or excessive or inappropriate guilt
8. Concentration: diminished ability to think or concentrate, or more indecisiveness
9. Suicidality: Thoughts of death or suicide, or has suicide plan

2. Clinical Features of Depression (Reus, 2015)

1. Depressed mood
2. Loss of interest or pleasure
3. Change in appetite or weight
4. Insomnia or hypersomnia
5. Fatigue or loss of energy
6. Psychomotor agitation or retardation
7. Feelings of worthlessness or inappropriate guilt
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 8. Decreased ability to concentrate and make decisions
9. Recurrent thoughts of death or suicide.

3. Risk Factors (Walker et al, 2014)

 Alcohol misuse
 Substance misuse
 Older age
 Previous history of depression or anxiety
 Lack of social support
 Medical condition that affect psycological factor:
o New diagnosis of a serious medical condition
o Deterioration of or failure of treatment for medical condition
o Unpleasant, disabling or disfiguring treatment
o Change in medical care, e.g. Discharge from hospital
o Impending death

4. Pathophysiology
At least three main categories of peripheral hormonetype factors, for which genetic
variants are associated with major depressive disorder, are implicated in the
pathophysiology of the illness: (1) neurotrophic factors and other growth factors,
including BDNF, vascular endothelial growth factor, and insulin-like growth factor-1; (2)
proinflammatory cytokines, including interleukin-1β, interleukin-6, and tumour necrosis
factor-α;and (3) impaired regulation of the hypothalamicpituitary-adrenocortical (HPA)
axis. For example, serum BDNF is decreased in individuals with major depression, and
antidepressant treatment reverses this decrease (Kupfer et al, 2012).

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 Shown in the figure are the hippocampus (HP) and amygdala (Amy) in the
temporal lobe, regions of prefrontal cortex， nucleus accumbens (NAc)， and
hypothalamus (Hyp). Only a subset of the known interconnections among these brain
regions is shown. Also shown is the innervation of several of these brain regions by
monoaminergic neurons. The ventral tegmental area (VTA) provides dopaminergic
input to each of the limbic structures. Norepinephrine (from the locus coeruleus [LC])
and serotonin (from the dorsal raphe [DR] and other raphe nuclei) innervate all of the
regions shown. In addition， there are strong connections between the hypothalamus
and the VTA-NAc pathway. Important peptidergic projections from the hypothalamus
include those from the arcuate nucleus that release ß-endorphin and melanocortin and
from the lateral hypothalamus that release orexin (Messing and Nestler, 2015).

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 Neuroimaging studies of major depressive disorder have provided evidence for
specific functional abnormalities in these neural systems in adults. Converging findings
from these studies suggest abnormally increased amygdala, ventral striatal, and medial
prefrontal cortex activity, mostly to negative emotional stimuli, such as fearful faces.
Abnormally reduced ventral striatal activity to positive emotional stimuli, and during
receipt and anticipation of reward in adults and adolescents with depression have also
been reported (Kupfer et al, 2012).

Brain area changes in major depressive disorder patient (Sacher, 2011)

Advances in neurobiology of Major Depressive Disorder (Kupfer et al, 2012)

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 Neuroendocrine abnormalities that reflect the neurovegetative signs and
symptoms of depression include: (1) increased cortisol and corticotropin -releasing
hormone (CRH) secretion， (2) an increase in adrenal size， (3) a decreased
inhibitory response of glucocorticoids to dexamethasone， and (4) a blunted
response of thyroid- stimulating hormone (TSH) level to infusion of thyroid-
releasing hormone (TRH). Antidepressant treatment leads to normalization of these
abnormalities. Major depression is also associated with changes in levels of
pro-inflammatory cytokines and neurotrophins (Reus, 2015)

Serotonin

(Barrett et al, 2010)

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(Nestler et al, 2009)

Serotonin Receptor Function (Pytliak et al, 2011)

Receptor Function (on activation)
5-HT1A CNS: Aggression, Anxiety, Addiction, Appetite, Emesis, Impulsivity,
Memory, Mood, Nausea, Nociception, Respiration, Sleep, Sociability,
Thermoregulation, Sexual behavior
Cardiovascular system: Blood pressure, Heart rate, Cardiovascular function,
Vasoconstriction, Penile erection
Other: Pupil dilation
5-HT1B CNS: Aggression, Anxiety, Learning, Addiction, Locomotion, Memory,
Mood, Sexual behavior
Vessels: Pulmonary vasoconstriction, Penile erection
5-HT1D CNS: Locomotion, Anxiety
Vessels: Cerebral vasoconstriction
5-HT1E CNS:Memory
5-HT1F Blood: Vessels:Vasoconstriction
CNS: Locomotion, Anxiety

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5-HT2A CNS:Anxiety, Appetite, Addiction, Cognition,Imagination, Learning,
Memory, Mood, Perception, Sexual behaviour, Sleep, Thermoregulation
Smooth muscles:Contraction
Vessels:Vasoconstriction, Vasodilation
Platelets:Aggregation
5-HT2B CNS:Anxiety, Appetite, Sleep
Gastrointestinal tract:GI motility
Vessels:Vasoconstriction
Cardiovascular system:Cardiovascular function
5-HT2C CNS:Anxiety, Appetite, Addiction, Locomotion, Mood, Sexual behaviour,
Sleep, Thermoregulation
Gastrointestinal tract:GI motility
Vessels:Vasoconstriction, Penile erection
5-HT3 CNS, PNS:Anxiety, Addiction,Anxiety, Nausea, Emesis, Learning, Memory,
Neuronal excitation
Gastrointestinal tract:GI motility, Nausea, Emesis
5-HT4 CNS:Anxiety, Appetite,Learning, Memory, Mood, Respiration
Gastrointestinal tract:GI motility
5-HT5 CNS:Locomotion, Sleep
(only
5-HT5A
receptor in
humans)
5-HT6 CNS:Anxiety, Cognition, Learning, Memory, Mood
5-HT7 CNS:Anxiety, Memory, Mood, Respiration, Sleep, Thermoregulation
Vessels:Vasoconstriction

Dopamine

(Barrett et al, 2010)

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(Nestler et al, 2009)

Dopamine Receptor Function (Beaulieu and Gainetdinov, 2011)

Receptor Function (on activation)
D1 Postsynaptic stimulatory effect on locomotor activity
D2 Decrease in dopamine release that results in decreased locomotor activity
D3 Exert a moderate inhibitory action on locomotion either by acting as
autoreceptors or through the involvement of postsynaptic receptor
populations
D4 and D5 Unknown. Has minor modulatory influence on
some specific aspects of cognitive functions that are mediated by
hippocampal areas

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5. Medical Algorithm (Reus, 2015)

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 Current Antidepressant Drug for Major Deppresion Disorder
Class
Selective Serotonin Reuptake
Inhibitors
Tricyclic antidepressant
Norephineprine-dopamine
reuptake inhibitor
Serotonin-norephineprine
reuptake inhibitor
Serotonin reuptake inhibitor and
5-HT1A receptor partial agonist
Drugs Mechanism of Action
Fluoxetine, fluvoxamine, Inhibit the reuptake of serotonin
sertraline (selective)
Amitriptyline, imipramine, Inhibit the reuptake of monoamine
maprotiline (non-selective)
Bupropion Inhibit reuptake of NE and
dopamine (non selective)
Duloxetine, venlafaxine, Inhibit reuptake of serotonin and
mirtazapine NE
Vilazodone Selectively reuptake serotonin and
partially agonist 5-HT1A
Physiological Effect
Increase serotonin level. Increase
mood, cognitive function
Increase serotonin, dopamine, and NE
level. Increase mood in depression
patient.
Increase NE and dopamin level.
Increase mood and cognitive function.
Increase serotonin and NE level.
Increase mood, cognitive function.
Increase 5-HT1A effect on CNS (mood,
aggresion, sleep, memory)

Antidepressant Adverse Drug Effect

Class
Selective Serotonin Reuptake Inhibitors
Tricyclic antidepressant
Norephineprine-dopamine reuptake inhibitor
Serotonin-norephineprine reuptake inhibitor
Adverse effect
Sexual dysfunction, insomnia, anxiety, nausea, weakness, xerostomia
α-block, M block, sedation, weight gain; Overdose: arrhythmias, seizures
Tachycardia, insomnia, headache, xerostomia, weight loss, nausea, dizziness
Anticholinergic, sedation, hypertension, appetite decrease, insomnia, constipation

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6. Recent Drug Development
Drug Mechanism Effect

Agomelatine Melatonin (MT1 and Increase sleep (REM and

MT2) agonist and a 5-HT2C-receptor NREM sleep), alter
antagonist neurotransmission of
serotonin, increase mood.
Vortioxetine 5-HT3A and 5-HT7 receptor antagonist, 5- Increae mood and inhibit
HT1B receptor partial agonist, 5-HT1A anxiety, locomotor function
receptor agonist and inhibitor of the serotonin
transporter

Agomelatine, a melatonin (MT1 and MT2) agonist and a 5-HT2C-receptor

antagonist. Agomelatine has shown a generally favourable tolerability and efficacy,
therefore providing a promising alternative for patients who do not respond to existing
pharmacotherapies, or who cannot tolerate their side-eff ects. Placebo-controlled
research provides evidence for the effectiveness of agomelatine as both an acute and a
continuation treatment for major depression (Kennedy et al, 2015).

Vortioxetine, an atypical antidepressant 5-HT3A and 5-HT7 receptor antagonist, 5-

HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the serotonin

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transporter, gotten approval to treat major depression as of September 2013. Recent
study demonstrated vortioxetine as effective as current antidepressant, duloxetine, with
tolerable side effects (Mahableshwarkar et al, 2014).

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 Daftar Pustaka

Barrett et al, 2010. Neurotransmitters & Neuromodulators. In:Ganong's Review of Medical

Physiology. 23ed
Beaulieu and Gainetdinov, 2011. The Physiology, Signaling, and Pharmacology of Dopamine
Receptors. Pharmacol Rev 63:182–217
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, 1994
Kennedy et al, 2015. Sustained efficacy of agomelatine 10 mg, 25 mg, and 25–50 mg on
depressive symptoms and functional outcomes in patients with major depressive
disorder. A placebo-controlled study over 6 months. Neuropsychopharmacology
Kupfer et al, 2012. Major depressive disorder: new clinical, neurobiological, and treatment
perspectives
Mahableshwarkar et al, 2014. A randomized, double-blind, duloxetine-referenced study
comparing efficacy and tolerability of 2 fixed doses of vortioxetine in the acute
treatment of adults with MDD. Psychopharmacology
Messing, R.O. and Nestler E.J., 2015. Biology of Psychiatric Disorders. In: Harrison’s
Principle of Internal Medicine 19th Ed
Nestler et al, 2009. Molecular Neuropharmacology: a foundation for clinical neuroscience.
2nd Ed
Pytliak et al, 2011. Serotonin Receptors – From Molecular Biology to Clinical Applications.
Physiol. Res. 60: 15-25
Reus, VI., 2015. Mental Disorder. In: Harrison’s Principle of Internal Medicine 19th Ed
Sacher et al, 2011. Mapping the depressed brain: A meta-analysis of structural and functional
alterations in major depressive disorder. J Affect Disord
Walker et al, 2014. Davidson’s Principles and Practice of Medicine. 22nd Edition

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