3- Antidepressant Agents
A- Intro
1- Neurotrophic hypothesis
‣ Studies show that pain and stress decrease the levels of BDNF which is a neurotrophic factor ->
atrophy happens in the hippocampus, medial frontal cortex ( integration of emotions and
attention) and anterior cingulate ( memory, learning and emotions ).
‣ Depression -> drop in BDNF levels in CSF + decrease in tyrosine kinase receptor B activity.
‣ Antidepressants -> increase BDNF levels -> may be increase in the hippocampus volume.
2- Monoamine hypothesis
‣ Depression is associated with low function of cortical and limbic serotonin, NE and DA.
‣ Reserpine decrease monoamines -> depression in some patis.
‣ Fluoxetine a serotonergic antidepressant when used by patis
with a diet free of tryptophan ( precursor of serotonin ) they
suffer from depression relapses.
‣ Desipramine a noradrenergic antidepressant does not cause relapses in patis with tryptophan
free diet but can cause relapses in patis with depleted catecholamines or administrating an
inhibitor of norepinephrine inhibitor.
‣ Genetic evidence: There is a polymorphism in the promoter region of serotonin transporter gene
, that regulates the number of this protein. Patis with homozygous for the S (short ) allele are
more prone to get depression and are harder to treat while patis with homozygous L ( long )
allele are more resistant to depression and are easier to treat.
‣ Drugs evidence: the strongest evidence which suggests that all antidepressants increase the
availability of monoamines in the synaptic junction.
3- Neuroendocrine hypothesis
‣ HPA axis and steroid abnormalities suppress the transcription of BDNF gene especially in
glucocorticoid sensitive parts of the brain like the hippocampus where it has lots of
glucocorticoid receptors therefore in prolonged stress states it may result in a decrease in BDNF
and volume loss.
‣ MDD is associated with High cortisol levels, ACTH abnormalities, high CRH
‣ 25% of depressed patis have abnormal thyroid function ( hypothyroidism )
‣ Estrogen de ciency states cause depression in some women
‣ Severe testosterone de ciency in men cause depression
‣ Hormone therapy is associated with improvement.
4- Integration of Hypotheses Regarding the Pathophysiology of Depression
‣ Hypotheses are not mutually exclusive because monoamine, neuroendocrine, and neurotrophic
systems are interrelated in important ways.
‣ The activation of monoamine receptors with antidepressant drugs
lead to the opposite effect of stress and increase BDNF + it down
regulate the HPA axis and normalize it.
‣ One of the weaknesses of the monoamine hypothesis is that drugs increase amine levels
A- Intro
1- Neurotrophic hypothesis
‣ Studies show that pain and stress decrease the levels of BDNF which is a neurotrophic factor ->
atrophy happens in the hippocampus, medial frontal cortex ( integration of emotions and
attention) and anterior cingulate ( memory, learning and emotions ).
‣ Depression -> drop in BDNF levels in CSF + decrease in tyrosine kinase receptor B activity.
‣ Antidepressants -> increase BDNF levels -> may be increase in the hippocampus volume.
2- Monoamine hypothesis
‣ Depression is associated with low function of cortical and limbic serotonin, NE and DA.
‣ Reserpine decrease monoamines -> depression in some patis.
‣ Fluoxetine a serotonergic antidepressant when used by patis
with a diet free of tryptophan ( precursor of serotonin ) they
suffer from depression relapses.
‣ Desipramine a noradrenergic antidepressant does not cause relapses in patis with tryptophan
free diet but can cause relapses in patis with depleted catecholamines or administrating an
inhibitor of norepinephrine inhibitor.
‣ Genetic evidence: There is a polymorphism in the promoter region of serotonin transporter gene
, that regulates the number of this protein. Patis with homozygous for the S (short ) allele are
more prone to get depression and are harder to treat while patis with homozygous L ( long )
allele are more resistant to depression and are easier to treat.
‣ Drugs evidence: the strongest evidence which suggests that all antidepressants increase the
availability of monoamines in the synaptic junction.
3- Neuroendocrine hypothesis
‣ HPA axis and steroid abnormalities suppress the transcription of BDNF gene especially in
glucocorticoid sensitive parts of the brain like the hippocampus where it has lots of
glucocorticoid receptors therefore in prolonged stress states it may result in a decrease in BDNF
and volume loss.
‣ MDD is associated with High cortisol levels, ACTH abnormalities, high CRH
‣ 25% of depressed patis have abnormal thyroid function ( hypothyroidism )
‣ Estrogen de ciency states cause depression in some women
‣ Severe testosterone de ciency in men cause depression
‣ Hormone therapy is associated with improvement.
4- Integration of Hypotheses Regarding the Pathophysiology of Depression
‣ Hypotheses are not mutually exclusive because monoamine, neuroendocrine, and neurotrophic
systems are interrelated in important ways.
‣ The activation of monoamine receptors with antidepressant drugs
lead to the opposite effect of stress and increase BDNF + it down
regulate the HPA axis and normalize it.
‣ One of the weaknesses of the monoamine hypothesis is that drugs increase amine levels
