Clinical pharmacology: introduction to depression

1. Introduction to depression
and antidepressant agents
Domina Petric, MD

2. Depression
• The diagnosis of depression rests primarily on
the clinical interview.
• Major depressive disorder (MDD) is
characterized by depressed mood most of the
time for at least 2 weeks and/or loss of
interest or pleasure in most activities.
• Depression is also characterised by
disturbances in sleep and appetite, as well as
deficits in cognition and energy.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

3. Depression
• Thoughts of guilt, worthlessness and suicide
are common.
• Coronary artery disease, diabetes and stroke
appear to be more common in depressed
patients.
• Depression may considerably worsen the
prognosis for patients with a variety of
comorbid medical conditions.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

4. Depression
• The primary indication for
antidepressant agents is the treatment
of MDD.
• MDD represents one of the most
common causes of disability in the
developed world.
• Major depression is commonly
associated with a variety of medical
conditions, from chronic pain to
coronary artery disease.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

5. Antidepressants are also used in the treatment of:
• panic disorder
• generalized anxiety disorder (GAD)
• posttraumatic stress disorder (PTSD)
• obsessive-compulsive disorder (OCD)
• neuropathic pain
• pain associated with fibromyalgia
• premenstrual dysphoric disorder
(PMDD)
• stress urinary incontinence
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

6. Pathophysiology of major depression
Monoamine hypothesis: deficit in
function or amount of monoamines.
Neurotrophic hypothesis: neurotrophic
and endocrine factors play a major role.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

7. Neurotrophic hypothesis
• Nerve growth factors such as brain-derived
neurotrophic factor (BDNF) are critical in the
regulation of neural plasticity, resilience and
neurogenesis.
• Depression is associated with the loss of
neurotrophic support.
• Effective antidepressant therapies increase
neurogenesis and synaptic connectivity in cortical
areas such as hippocampus.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

8. Neurotrophic hypothesis
• BDNF is thought to exert its influence on neuronal
survival and growth effects by activating the
tyrosine kinase receptor B in both neurons and glia.
• Stress and pain are associated with a drop in BDNF
levels.
• This loss of neurotrophic support contributes to
atrophic structural changes in the hippocampus and
maybe other areas, such as the medial frontal
cortex and anterior cingulate.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

9. Neurotrophic hypothesis
The hippocampus is important both in
contextual memory and regulation of the
hypothalamic-pituitary-adrenal (HPA) axis.
The anterior cingulate plays a role in the
integration of emotional stimuli and attention
functions.
The medial orbital frontal cortex plays a role
in memory, learning and emotion.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

10. Neurotrophic hypothesis
• Major depression is associated with a 5-10% loss of
volume in the hippocampus.
• Depression and chronic stress states have also been
associated with a substantial loss of volume in the
anterior cingulate and medial orbital frontal cortex.
• Loss of volume in structures, such as the
hippocampus, appears to increase as a function of
the duration of illness and the amount of time that
the depression remains untreated.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

11. Neurotrophic hypothesis
• Depression appears to be associated with a
drop in BDNF levels in the cerebrospinal fluid
and serum, as well as with a decrease in
tyrosine kinase receptor B activity.
• Administration of antidperessants increases
BDNF levels and may be associated with an
increase in hippocampus volume in some
patients.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

12. Monoamine hypothesis
• The monoamine hypothesis of depression
suggests that depression is related to a
deficiency in the amount of function of
cortical and limbic serotonin (5-HT),
norepinephrine (NE) and dopamine (DA).
• Reserpine depletes monoamines: treatment
with reserpine is associated with depression
in a subset of patients.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

13. Monoamine hypothesis
• A functional polymorphism exists for the
promoter region of the serotonin transporter
gene.
• This gene regulates how much of the transporter
protein is available.
• Subjects who are homozygous for the short
allele may be more vulnerable to developing
major depression and suicidal behavior in
response to stress.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

14. Monoamine hypothesis
All available antidepressants appear to have
significant effects on the monoamine
system.
All classes of antidepressants appear to
enhance the synaptic availability of
5-HT, norepinephrine or dopamine.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

15. Neuroendocrine factors
• Depression is associated with a number of
hormonal abnormalities.
MDD is associated with:
• elevated cortisol levels
• nonsuppression of adrenocorticotropic hormone
(ACTH) release in the dexamethasone suppression
test
• chronically elevated levels of corticotropin-
releasing hormone
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

16. Neuroendocrine factors
• More severe types of depression, such as
psychotic depression, tend to be associated
with HPA abnormalities more commonly than
milder forms of major depression.
• Both exogenous glucocorticoids and
endogenous elevation of cortisol are
associated with mood symptoms and cognitive
deficits similar to those seen in MDD.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

17. Neuroendocrine factors
• Up to 25% of depressed patients are reported to
have abnormal thyroid function.
• These include a blunting of response of
thyrotropin to thyrotropin-releasing hormone
and elevations in circulating thyroxine during
depressed states.
• Clinical hypothyroidism often presents with
depressive symptoms, which resolve with
thyroid hormone supplementation.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

18. Neuroendocrine factors
• Thyroid hormones are also commonly used in
conjunction with standard antidepressants to
augment therapeutic effects of antidepressants.
• Estrogen deficiency states, which occur in the
postpartum and postmenopausal periods, may
play a role in the etiology of depression in some
women.
• Severe testosterone deficiency in men is
sometimes associated with depressive symtpoms.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

19. Neuroendocrine factors
Hormone replacement therapy
in hypogonadal men and
women may be associated
with an improvement in mood
and depressive symptoms.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

20. Integration of hypotheses
• Monoamine, neuroendocrine and neurotrophic
systems are interrelated in important ways.
• HPA and steroid abnormalities may contribute to
suppression of transcription of the BDNF gene.
• Glucocorticoid receptors are found in high density in
the hippocampus.
• Binding of these hippocampal receptors by cortisol
during chronic stress states may decrease BDNF
synthesis and may result in volume loss in stress-
sensitive regions (for example, hippocampus).
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

21. Integration of hypotheses
• The chronic activation of monoamine receptors by
antidepressants appears to have the opposite effect
of stress: increase in BDNF transcription.
• Activation of monoamine receptors appears to
down-regulate the HPA axis and may normalize HPA
function.
• Amine levels increase immediately with
antidepressant use.
• Protein synthesis of BDNF typically takes 2 weeks or
longer.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.

22. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
Katzung, Masters, Trevor. Basic and clinical
pharmacology.