Major Depression Disorder Flashcards
MDD at a glance
MDD is a debilitating disease that is
characterized by depressed mood,
diminished interests, impaired cognitive
function and vegetative symptoms, such as
disturbed sleep or appetite.
Occurs about twice as often in women than
it does in men and affects one in four-to-six
adults in their lifetime.
Etiology is multifactorial. Heritability is
estimated to be ~35%. Also, environmental
factors, such as sexual, physical or
emotional abuse during childhood, are
strongly MDD risk factors.
No established mechanism can explain all
aspects of the disease.
Relative risk (RR) of various diseases is increased in
those with major depressive disorder (MDD)
compared with those who do not have MDD.
Differential diagnosis:
* Schizophrenia
* Bipolar disorder
MDD Epidemiology
Prevalence and main correlates
There were over 298 million cases of MDD globally at any point in time in
2010, with the highest proportion of cases occurring between 25-34y.
12-month MDD prevalence was similar in ten high-income (5.5%) and eight
low-income and middle-income (5.9%) countries. Income is not a correlate.
Discrepancy exist between countries in terms of resources and treatments
available. 50-60% MDD patients receive treatments in high-income countries,
<10% in low-income countries.
Regions in conflict have higher prevalence than those without.
Higher in females (5.0–6.0%) compared to males (3.0–3.6%) in a WHO 2010
survey. Same in other surveys.
The course of MDD is pleomorphic, with considerable variation in remission
and chronicity; chance of MDD recurrence is high, as about 80% of patients in
remittance experience at least one recurrence in their lifetime.
MDD risk increases significantly after SARS-CoV-2 infection. 80% of
individuals afflicted with the virus on a long-term basis (‘long COVID’) have a
mild to moderate form of depression.
MDD pathophysiology
Multiple Biological Systems
The central nervous system, as well as major stress response
systems, such as the hypothalamic–pituitary–adrenal (HPA) axis,
the autonomic nervous system and the immune system, are
involved in MDD.
In the CNS, altered neurotransmission and reduced plasticity are
evident. These could underlie functional changes in relevant
brain circuits such as the affective–salience networks.
Chronic MDD impairs HPA axis feedback regulation, one of the
most consistently reported biological features of MDD.
In the immune system, circulating cytokines and low-grade
chronic activation of innate immune cells, including monocytes.
Once chronic, both HPA axis hyperactivity and inflammation
converge on the autonomic nervous system to contribute to CNS
pathobiology as well as cardiovascular and metabolic disease,
which often co-occur with MDD
Biological basis of MDD
Subcallosal cingulate
cortex/ BA25:
Activated during
depression or while
recalling sad
memories.
Brodmann’s area 25
(Rich in Serotonin transporters)
BA25 is connected extensively to the brain
stem and hypothalamus (hunger etc.), the
amygdala and insula (mood and anxiety);
the hippocampus (memory), and certain
parts of the frontal cortex.
PET scan of depressed patient showing hyperactivity
of BA25 (subcallosal cingulate cortex).
Other brain-based characteristics:
* Impaired coordination of
interactions within and between
segregated limbic (affective–
salience circuits) and cortical neural
networks.
* More activation of default mode
network (DMN); active during
relative rest, mind-wandering and
inward-directed mental activity).
This underpins features like
negative self-focus and ruminative
tendencies
* Increased functional connectivity
between BA25 and DMN isseen in
MDD; predictive of higher levels of
depressive rumination.
Etiology of MDD
A complex array of genetic and environmental factors
influence whether a person develops depression.
Major depressive disorder is governed by the concerted
action of interrelated molecular pathways and physiological
activities.
The relative contribution of each pathway varies between
individual patients as a reflection of the high complexity of
the disease.
A complete understanding of the associations of the
multiple molecular pathways with MDD may be an
unrealistic expectation
Monoamine hypothesis
Serotonin, Noradrenaline, and Dopamine
The monoamine hypothesis posits that
neurotransmission is attenuated due to lack of
adequate modulatory neurotransmitters, such as
serotonin and dopamine.
Serendipitous discovery 50y ago by Bloch et al. of the
first drug with antidepressant effects (isoniazid and
iproniazid, weak MAO inhibitors).
Variable efficacy. SSRIs, for example, are effective only
in 30-40% patients. ‘
Non-specific and/or adverse effects are abundant.
E.g., Serotonin syndrome.
MAOIs and TCAs are not commonly used due to the
high incidence of side-effects and lethality in overdose.
For e.g., TCAs, to varying degrees, are potent blockers
of histamine H1 receptors, serotonin 5-HT2 receptors,
muscarinic acetylcholine receptors, and a1-adrenergic
receptors.
The Glutamate hypothesis
An alternative to the monoamine hypothesis
The NMDA receptor antagonist Ketamine has rapid (within hours)
and potent antidepressant effects in treatment-resistant major
depressive disorder and bipolar depression.
A single subanesthetic dose of the dissociative anesthetic induces
rapid and sustained antidepressant actions in treatment-resistant
patients.
Racemic (IV) ketamine and Esketamine (Spravato) are FDA
approved for treating treatment-resistant depression.
Possible underlying mechanism(s):
* Ketamine is hypothesized to specifically inhibit extra-synaptic GluN2B-
NMDARs. No anti-depressant effect of Ketamine on mice lacking GluN2B.
* Disinhibition via GABAergic interneurons (increased overall activity in the
prefrontal cortex).
* Inhibition of extrasynaptic NMDA-Rs (helps protein synthesis)
* Inhibition of spontaneous NMDA-R activity (increases BDNF translation)
* NMDAR inhibition-independent mechanisms via metabolites (e.g., HNK, a
Ketamine metabolite, promote AMPA-R currents).
Ketamine beyond the NMDA receptor
Neurotrophins in anti-depressant synaptogenesis
Some studies indicate, it is unlikely that
NMDAR plays a major role in the
antidepressant action of (R,S)-ketamine
and its enantiomers.
Alternatively, it may act by promoting
brain-derived neurotrophic factor (BDNF,
a neurotrophin) and it’s signaling.
Multiple lines of evidence suggest that
BDNF and its receptor tropomyosin
receptor kinase B (TrkB) play a crucial role
in depression and in the therapeutic
mechanisms of antidepressants.
Several antidepressants, including SSRIs
and ketamine, directly bind to TRKB.
GPCR-based
novel antidepressants
- Instead of designing a highly specific and tailored
ligand for one receptor (i.e., a magic bullet), targeting
one cell population and pathway, approaches have
been made to pursue several targets with one
compound (“Polypharmachology”). - DREADD: Designer receptors
- One can target receptors or common components of
intracellular signaling. E.g., p11, which forms a
heterotetrameric scaffold at cell membrane and
interacts with receptors of several systems (see beside)
and regulate their localization and function. Loss of p11
correlates with increased despair in behavior
(depression). Several SSRIs upregulate p11. In theory,
one could viral-deliver the p11 gene to MDD patients
and upregulate p11 levels to ameliorate the disease
Sex differences in depression
Circuits and mechanisms
Epidemiological sex differences MDD are well
characterized. Yet the circuits and mechanisms that
contribute to these differences are understudied,
because preclinical studies have historically excluded
female rodents.
Recent studies have identified male- and female-
specific circuit vulnerabilities in MDD. See some
examples in the top panel.
When sexes are compared, there are instances where
the same circuit is engaged, but the response is larger
or longer lasting in one sex than the other. For
example, in the lower panel on the right, stress-
induced corticotropin-releasing factor (CRF) causes
greater activation of the locus coeruleus (LC, primary
source of norepinephrine) arousal system in females
than males (hyperarousal). Leads to PTSD like
symptoms, followed by depression.
