Monoamine hypothesis of Depression

Question 1

Write an introduction for critically discussing the monoamine hypothesis of depression

Answer 1

• The monoamine hypothesis of depression states that depression is due to absolute or relative deficiencies in monoamine neurotransmitters, particularly noradrenaline (NA) and serotonin (5HT) (Sanacora et al., 2012).
• This first arose following the effectiveness of iproniazid to “energise” depressed patients (Maxwell et al., 1990), therefore being considered the first antidepressant.
• Iproniazid belong to the monoamine inhibitor (MAOI) drug class, which forms the basis of the widespread monoamine hypothesis of depression.
• However, newer drugs developed to reverse monoamine deficiencies have yet to provide a universal pharmacological solution for depression.
• Overall treatment effects are only moderate, with one-third of patients not responding to monoamine-based treatments (Duman & Aghajanian, 2012).
• This essay will critically discuss the monoamine hypothesis through outlining its supporting evidence; criticisms; and current alternative hypotheses.

Question 2

Outline the DSM-4 criteria of depression. Discuss the revelance of monoamines.

Answer 2

• Core symptoms of depression as per the DSM-4 include persistent sadness or low mood, and loss of interest or pleasure in most activities.
• Additional symptoms consist of fatigue, guilt, suicidal ideation, and cognitive deficits.

Question 3

Discuss evidence for a role of NA in depression

Answer 3

• NA plays a role in responsiveness and sensitivity to the environment (Garrett, 2015).
• Deficits may contribute to psychomotor retardation, amotivation, and unresponsiveness to environmental change seen in depression (Siever et al., 1991).
• However, post-mortem findings of depressed patients is weak, as there is little evidence of reduced NA receptors or function (Young, 2019).
• NA metabolistes appear to increase following antidepressant treatment, but fail to show consistent decreases amongst depressed patients (Young, 2019).

Question 4

Discuss the evidence for a role of serotonin in depression

Answer 4

• Serotonin is a widespread neurotransmitter with extensive effects including mood, activity level, sleep, sexual activity, cognitive function, and emotionality (Siever et al., 1991), all of which can be impaired in depression.
• Studies supporting a role of 5-HT found its metabolite to be associated with violent suicide attempts (Young, 2019), with a variety of newer sertonin-based antidepressants increasing synaptic serotonin.
• However, there is no consensus of 5HT metabolite being associated with other depressive symptoms, and reduced 5HT is not a consistent finding amonst depressed patients (Young, 2019).

Question 5

Discuss the evidence for a dopamine hypothesis of depression

Answer 5

• The final monoamine, dopamine, recieves little attention regarding depression.
• Inconsistent therapeutic results from DA agonists, such as amphetamines, (Garrett, 2015) suggest the monoamines relating to depression are primarily NA and 5HT.

Question 6

Discuss the major criticisms to the monoamine hypothesis

Answer 6

• The predominant criticism of the hypothesis is temporal discrepancy between the immediate effects of antidepressants on monoamine availability versus the delayed therapeutic effects (Sanacora et al., 2012).
• Other criticisms include:
  
  • Failure of experimental monoamine depletion to alter mood in healthy controls (Ruhe et al., 2007);
  • Maladaptive enhancements to DA and 5HT that strengthen memories of aversive life events in animal models (Krishnan et al., 2007); &
  • Opposing region-specific neurotransmitter-induced effects (Krishnan & Nestler, 2008).

Question 7

Describe why the monoamine hypothesis is too simplistic

Answer 7

• These suggest the current monoamine hypothesis is overly simplistic.
• Although the mechanisms of current antidepressants elevate synpatic monoamines, the lack of effective in 1/3 of patients (Duman & Aghajanian, 2012) implicates monoamine deficiencies are insufficient to singlehandedly account for depression.
• Transpcription factors (e.g. CREB), involved in intracellular communications following postsynaptic monoamine binding, show upregulation in both antidepressant treatment and depression-like responses depending on the brain area (Carlson, 2010).
• This region-specfic difference suggests there is more nuance than general monoamine depletion causing depression.

Question 8

Suggest an alternative hypothesis of depression

Answer 8

• Serum glucocorticoids and cytokines provide insight into comorbid depression in Cushing’s syndrome and immunocompromised conditions respectively (Krishnan & Nestler, 2008).
• New breakthrough research has identified Ketamine as a potent antidepressant for treatment-resistant cases (Zarate et al., 2006) and bipolar depression (Duman & Aghajanian, 2012).
• Regarded as arguably the most important discovery in decades (Duman & Aghajanian, 2012), this suggest an alternative glutamate/neuroplasticity hypothesis that relegates monoamines to a secondary role.

Question 9

Discuss evidence supporting a glutamate hypothesis

Answer 9

• Ketamine is a NMDA glutamate receptor antagonist, a drug class known to possess antidepressant properties since the early 1990s, with glutamate receptors modulated by MAOIs (Sanacora et al., 2012).
• Glutamate is the primary excitatory neurotransmitter in the brain, found to be abnroamlly regulated in limbic/cortical areas of depressed individuals (Sanacora et al., 2012).
• A single infusion of ketamine was found to alleviate treatment-resistant depression in 68%, which persisted for 7 days in 46% of patients (Murrough et al., 2013).
• Ketamine research has found associated with increased brain-derived neurotrophic factors (BDNFs) influencing neurogenesis, and reversal of chronic stress-induced brain atrophy (Duman & Aghajanian, 2012).
• Exciting research as of April this year identifies how ketamine recoers lost dendritic spines to sustain remission of depression (Moda-Sava et al., 2019).

Question 10

Conclude the critical discussion of the monoamine hypothese of depression

Answer 10

• In conclusion, the monoamine hypothesis of depression is outdated and insufficient to explain the complex pathophysiology of depression.
• Evidence suggests monoamines are important for the symptomology of depression, and increasing monoamine availablity can produce clinical improvement.
• Yet, its largest criticism is the temporal discrepancy between immediate altered monoamine levels and delayed therapeutic effects.
• The success of MAOIs in only 1/3 of depressed patients leaves much room for improvement.
• New breakthrough research, around the potent effects of Ketamine, provide a more complete glutamate/neuroplasticity hypothesis.
• The temporal discrepancy occurs due to longer-term neuroplasticity changes induced by monoamines.
• Finally, glutamate-based drugs have shown successful effects on treatmetn-resistant cases where monoamine-based drugs have failed.