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Depression
“Mental disorder that presents with depressed mood, loss of interest or pleasure, feeling of guilt or low self-worth, disturbed sleep or appetite, low energy, and poor concentration”. (WHO)
According to center for disease control and prevention (CDCP) survey in 2007, it is noticed that the most commonly prescribed drugs were antidepressants.
Risk factor / association
Not only it is a risk factor for diseases like diabetes and stroke but also with chronic diseases, as leads to depressed state, including pain, cancer, arthritis, diabetes, heart diseases.
Pathophysiology
Older theory
Monoamine Hypothesis
Although still commonly accepted, others are accepted as well. According to this
Depression is caused by deficiency or decreased levels of monoamines, serotonin, norepinephrine, dopamine at neuronal synapses.
Due to this deficiency in amount, depression of special areas occurs, including cortical and limbic areas of CNS.
Evidence
- Diet
It was noted that patients when given diet free of tryptophan (precursor of serotonin synthesis), have chances of relapse, if on serotonin antidepressants
On the other hand, of on noradrenaline anti-depressants, tryptophan free diet has no effect, because of different pathway.
- Drugs
Drugs decrease the synthesis of amines (reserpine –central sympathoplegic) cause depression in patients.
- Genetic studies polymorphism (s/l allele)
Patients having polymorphism in serotonin transporter gene S or short allele (homozygous) type of transporter such that there will be vulnerable depression due to stress due to resistance to serotonergic antidepressants.
Serotonin transporter has decreased serotonin at synaptic level.
Patients having L or long alleles are resistant to depression in response to stress.
- Receptors
It has been seen that if mutation, change or alteration occurs in the serotonin/norepinephrine receptor (alpha 2 esp.) this leads to changes in mood of patient.
- Existing antidepressants
Most convincing is that all existing antidepressants act by increasing the levels of monoamines at synaptic cleft
Although drugs at other sites have been tried, still no drug has been attained with clinical effectiveness.
Some other studies have opposite results. Even in depressed patients, increased levels of monoamines have been seen.
Larger body is in support of monoamine theory.
Drugs that increase the monoamine levels are given which increase levels immediately. Effective concentration is achieved after 2-3 weeks.
Delay in response
This lead to postulation that monoamines do not have direct effect but act through other mediators responsible for delayed response, which lead to the formation of new hypothesis.
Neurotropic Hypothesis
Certain neurotropic growth factors in brain are responsible for neuronal synaptic connectivity and plasticity which enhance neurogenic transmission.
Brain derived neurotropic factor has been isolated and mostly studied, it acts through tyrosine kinase receptor B by activating enzymes that leads to transcription of certain genes, which are in turn responsible for enhanced synaptic plasticity and connectivity.
Neurogenesis
In depressed state, neurons have less synaptic cleft connection, when treated, increase in BDNF results, leading to increased sprouting and increased neurogenesis and neuronal connectivity.
Decreased BDNF leads to atrophic changes in certain areas of brain responsible for depressed state. Special areas where BDNF is critical include
- hippocampus,
- hypothalamus pituitary axis,
- anterior cingulate area (attention) and
- medial orbital frontal cortex (memory, learning, emotions)
monoamines cause increase in BDNF levels, this leads to increased neurogenesis and synaptic connectivity.
Evidence – Animal models / clinical trials
Evidence comes from animal studies and clinical trials.
– Direct infusion
Direct infusion of BDNF in areas lead to enhanced neurogenesis and improved mood of animals. existing antidepressants
Existing antidepressants when used chronically, lead to increased BDNF in CSF and serum. Histological studies in animals in these areas indicate increased neurogenesis, increased volume of neuronal mass.
Studies not in favor include:
BDNF knockout mice
BDNF knocked out mice have been developed (genes knocked out) still do not show depression.
Some other regulatory mechanism might be present.
Polymorphism exists and BDNF might be responsible for variable response produced in these animals.
Other factors responsible include:
Neuroendocrine Factors
Hormonal imbalance leads to depression.
HPA axis dysregulation
If increased levels of corticotrophin releasing hormone , ACTH or cortisol occur, either endogenous or exogenous, produce depression.
Thyroid dysregulation
Also related with depression esp. hypothyroidism (thyroxin given in addition to antidepressants)
Sex hormones – estrogen / testosterone
Sex hormone deficiency also leads to depression. In hypogonadism patients are given hormone replacement therapy.
Integrated Regulation
All these theories are integrated. Not one factor is responsible for depression alone, all have their role.
BDNF gene transcription – HPA axis
BDNF transcription is suppressed by cortisol. HPA axis dysfunction is responsible for depression.
Monoamine receptor activation
Monoamine activators serotonin and alpha 2 receptors activation leads to increased BDNF gene transcription, which leads to improvement of depressed state.
Monoamine activation also normalizes HPA axis.
Glucocorticoid receptors – hippocampus
In hippocampal area, it is noted in depression that glucocorticoid receptors number is increased, responsible for depressive effects.
Classification
Selective Serotonin Reuptake Inhibitors (SSRIs)
Serotonin-Norepinephrine Reuptake Inhibitors
Tricyclic anti-depressants (TCAs)
5-HT2 Antagonists
Tetracyclic & Unicyclic antidepressants
Monoamine Oxidase Inhibitors
Irreversible / nonselective (selective for MAO B, in higher dose both A and B)
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Selective Serotonin Reuptake Inhibitors
Serotonin Norepinephrine Reuptake Inhibitors
