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

2. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
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. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.
Katzung, Masters, Trevor. Basic and clinical pharmacology.