Medical Pharmacology: Drugs Used to Manage Depression

Anatomical associations in depressive disorder

Certain regions of the brain have been associated with depression symptomatology.^26,75

**Brain Areas Associated or Affected in Depression⁷⁸**

"Many areas of the brain appear to be involved in depression including the frontal and temporal lobes and parts of the limbic system including the cingulate gyrus. However, it is not clear if the changes in these areas cause depression or if the disturbance occurs as a result of the etiology of psychiatric disorders."⁷⁸

The most consistent finding is reduced metabolism in the left frontal cortex. Other metabolic abnormalities have been identified in the cingulate and orbitofrontal cortices, hippocampus and elements of the medial limbic system.
Limited observations of mood changes associated with electrical stimulation of the brain have suggested other potential important anatomical regions.
- For example, stimulation of the left substantia nigra (as part of treatment for Parkinson's disease) resulted in a depressive state.
  - In other studies, stimulation of the subthalamic nucleus induced a reversible manic state.⁷⁶
At the cellular level, both depletion and alterations in pyramidal neurons associated with the CA3 region of the hippocampus appeared associated with stress and depression.^77,80

Pathophysiology

Biogenic amines appear involved in the biology of depression.²⁶

These amines include norepinephrine, dopamine, and serotonin.

Norepinephrine
Dopamine
Serotonin

**Brain Dopamineric and Serotoneric Pathways⁸³**

"Dopamine is transmitted via three major pathways. The first pathway extends from the substantia nigra to the caudate nucleus-putamen (neostratum) and is concerned with sensory stimuli and movement. The second pathway projects from the ventral tegmentum to the mesolimbic forebrain and is thought to be associated with cognitive, reward and emotional behavior. The third pathway, known as the tubero-infundibular system, is concerned with neuronal control of the hypothalamic-pituitary endocrine system."⁸⁴

Many antidepressant medications appear to in some way modulate these chemicals.
- Tricyclic antidepressants and monoamine oxidase inhibitors (MAOI) increase both norepinephrine and serotonin levels at central adrenergic sites in the limbic system and hypothalamus.
- Reserpine, which depletes norepinephrine, may induce a depressive state. From these sorts of observations, clinically important mechanism of action might be related to these neurochemical effects.

Subsequent to these observations another group of psychoactive agents were neurochemically described as serotonin-specific reuptake inhibitors (SSRIs).²⁶
- These agents also exhibit efficacy in management of depression.
Substance P has also been suggested as an important biomolecule in depression.^26,81
- This suggestion was based on:
  - Substance P brain localization
  - Antidepressant effects were noted in patients treated with a substance P antagonist.
  - Substance P antagonists did not appear to interact with monoamine systems in a manner similar to established antidepressant agents.⁸¹
Mechanistically one challenge is a resolution of why on one hand, neurochemical effects can be observed very quickly following drug administration and on the other improvement in depressive symptoms may take many weeks. This issue will be addressed shortly.²⁶
Depression may also reflected disorder in the hypothalamic-pituitary-adrenal axis.⁸²
- Higher levels of glucocorticoids might impede neurogenesis in the medial temporal lobe which might be related to the hippocampal neuronal loss identified in deceased, depressed patients.²⁶

Theories of Depression:²

Biological:
- An important biological theory of depression centers considers the apparent relationship between mood and monoamines.²
  - This idea followed from an observation that the drug isoniazid (Tybizid, Laniazid, Nydrazid) exhibited not only antitubercular effects but also a mood elevating effect.
    - Isoniazid (Tybizid, Laniazid, Nydrazid)
    - Isoniazid was identified as an inhibitor of monoamine oxidase, an enzyme which normally degrades and inactivates monoamines.
      - Inhibiting this enzyme would be expected to increase synaptic norepinephrine concentrations.
      - Depression thus might be due to reduced neurotransmitter levels which might in turn be rectified by monoamine oxidase inhibition.
- Changes in synaptic neurotransmitter concentrations usually occur soon after drug administration; however, clinical antidepressant effects are delayed, often for many weeks.²
  - One possible explanation was that antidepressant treatment, both drug and electroconvulsive therapy (ECT) might change the sensitivity of the norepinephrine receptor-coupled adenylate cyclase system.
  - This effect was associated with a reduced number or density of ß-adrenergic receptors and this process correlated with the delay associated with antidepressant effects.
- This theory does not preclude antidepressant effects closely tied to neurotransmitter levels as will be discussed.²
  - In addition, current models include a number of possible intracellular signals which regulate neuronal responses central to a comprehensive molecular understanding of antidepressant mechanisms.
  - Changes in mood may involve alterations not only neurotransmitters but also in hormones and neuropeptides.
    - Other neurotransmitters of possible importance in this setting include histamine, melatonin, GABA (gamma-aminobutyric acid), acetylcholine, and glycine.
    - Important hormones include both adrenal hormones and thyroid hormones; whereas neuropeptides that may modulate mood include enkephalins, endorphins, cholecystokinin, substance P, vasopressin and corticotropin-releasing hormone.²

Neuroendocrine:²

Onset of depression may be preceded by emotional trauma and emotional trauma may be also associated with effects on the neuroendocrine system.²

Adverse experiences during childhood, including abuse, neglect or loss, increase the likelihood of developing major depression in adulthood.
- This increased is especially prominent when additional challenges are also presented.
Both animal studies and clinical study results suggest that early stress, which occurs during periods of increased neuronal plasticity during development, may induce a long-term hyperactivity of CNS corticotropin-releasing hormone circuits as well as both sensitization of the HPA axis and autonomic nervous system responses to later stress.
- Variations in the corticotropin-releasing hormone receptor 1 (CRHR1) may moderate depression development following childhood trauma.
  - Corticotropin-releasing hormone receptor 1 protein⁸⁶
  - Allelic variation of the CRHR1 gene, focusing on the rs110402 single nucleotide polymorphism (SNP) located in intron 2 appears to protect against developing adult depression following moderate- severe childhood abuse.
  - Furthermore, there appears to be a sex difference in the risk to develop depression, given that women are more likely to suffer from depression and general and more frequently develop depression associated with childhood trauma.
    - The A allele of the rs11042 SNP appears associated with reduced depression symptoms among male subjects exposed to moderate-severe childhood abuse; moreover, this protective action does not appear president female subjects with childhood abuse exposure.
Also, hyperthyroidism and Cushing's syndrome may frequently affect mood.²
- Thyroid System⁸⁹
- Definitive characterization of the relationship between endocrine changes and psychological effects remains to be determined.

The hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-thyroid (HPT) axis represent the two primary endocrine systems of interest in psychiatry.²

**Hypothalamic-Pituitary-Adrenal (HPA) Axis⁸⁵**

"The hypothalamic-pituitary-adrenal (HPA) axis is a feedback loop that includes the hypothalamus, the pituitary and the adrenal glands. The main hormones that activate the HPA axis are Corticotropin-releasing factor (CRF), Arginine vasopressin (AVP) and Adrenocorticotropin hormone (ACTH). The loop is completed by the negative feedback of cortisol on the hypothalamus and pituitary. The simultaneous release of cortisol into the circulation has a number of effects, including elevation of blood glucose for increased metabolic demand. Cortisol also negatively affects the immune system and prevents the release of immunotransmitters. Interference from other brain regions (eg hippocampus and amygdala) can also modify the HPA axis, as can neuropeptides and neurotransmitters."⁸⁵

**Hypothalamic-Pituitary-Thyroid Axis⁸⁸**

HPT: hpothalamic-pituitary-thyroid TSH: thyrotropic-stimulating hormone CRH: corticotropin-releasing hormone LC: locus coeruleus NE: norepinephrine TRH: thyrotropin-releasing hormone T₃: triiodotyronine T₄: thyroxine

About 50% of depressed patients exhibit elevated cortisol levels, which return to normal values following resolution of depression.
- Cortisol hypersecretion is suggested based on:
  - Enhanced ACTH (adrenocorticotropin) secretion
  - Increased cortisol plasma levels
  - Changes in circadian rhythm of cortisol release
  - Resistance to glucocorticoid negative feedback inhibition of ACTH secretion
  - Reduced ACTH response to corticotropin-releasing hormone and
  - Analysis of cortisol (and metabolite(s)) in urine.
    - Antidepressant effects following anti-glucocorticoid drugs such as metyrapone, aminoglutethimide, and ketoconazole have been reported in some patients. Recall that not all depressed patients exhibit elevated cortisol.²
      - Pexacerfont is an example of a corticotropin releasing factor antagonist which is being evaluated in clinical trials for management of anxiety disorders; this agent may be useful for treatment of depression.⁸⁷
        
        Pexacerfont

Thyroid hormone influences brain development, synaptic conductivity and maturation.²
- In addition, thyroid hormones may affect mood.²
  - Some effects: With adult hypothyroidism, cognitive decline and depression are the most commonly noted psychiatric symptoms.
    - Also, antidepressant therapeutic action may be accelerated by concurrent administration of low-dose triiodothyronine (T₃).
      - T₃ (Liothyronine)
      - Sometimes addition of low-dose T₃ may transition a non-responding antidepressant-receiving patient to a responding patient.
      - Depressed patients exhibit reduced serum thyroxine (T₄) levels when these patients receive antidepressants, lithium, ECT or experience sleep deprivation.
        
        T₄ (Levothyroxine)
        
        Thyrotropin-releasing hormone (TRH) may induce a sense of well-being and relaxation in both normal patients as well as those with neurological or psychiatric disorders, notably in depression.²
        
        TRH: Protirelin

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