Treatments of Depression

Question 1

Understand theories about biological basis for depression

Answer 1

Neurotransmitter Dysfunction: Depression has been liked to dysregulation of neurotransmitters, particularly serotonin, norepinephrine and dopamine (Blier, 2013)

Neuroendocrine Factors: HPA axis regulate stress response through cortisol secretion

• Elevated cortisol levels observed in the dexamethasone suppression test (DST), where patients with depression show lack of normal cortisol suppression following dexamethasone administration (Asnis et al., 1989)
• Altered HPA axis feedback may lead to chronic stress response contributing to the onset of depressive symptoms due to decreased serotonin function (Porter et al., 2004)

Genetic Factors: The gene SLC6A4 encodes the serotonin transporter protein, which is responsible for re-uptaking serotonin from the synaptic cleft back into the presynaptic neuron. Variation in this gene, particularly the 5-HTTLPR polymorphism have been associated with susceptibility to depression, expecially when coupled with stressful life events

• 5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.
• One or two copies of the short allele of the 5-HTTLPR polymorphism exhibited more depressive symptoms. (Caspi et al., 2003)

Neuroplasticity and Brain Structure: Reduced hippocampal volume, and impaired neuronal plasticity are also associated with depression (Nestler et al., 2002)

• Neurotrophic Theory propose that depression is linked to reduced neurogenesis, particularly in the hippocampus, region invovled in mood regulation and cognitive functions. Decreased levels of BDNF = decreased neuron growth and plasticity; treatments for depression have been shown to increase BDNF levels (Lee et al., 2007; Wolkowitz et al., 2011)

Question 2

Understand the monoamines theory and beyond

Answer 2

Monoamine Theory

Depression is primarily due to a deficiency in certain neurotransmitters in the brain:

Serotonin: Low levels correlated with feelings of depression, anxiety and aggressive behaviour

Norepinephrine: Deficits may contribute to the lethargy and fatigue often seen in depression

Dopamine: Essential for motivation, pleasure, and reward. Low dopamine is associated with anhedonia, a core symptom of depression where individuals no longer find pleasure in enjoyable activities

The evidence for the monoamine theory initially stemmed from the accidental discovery that certain drugs increased monoamine levels in the brain and alleviated depressive symptoms. Subsequently, antidepressants such as tricyclics and monoamine oxidase inhibitors (MAOIs) were developed to increase the levels of these neurotransmitters.

(Goldberg et al., 2014)

Beyond

Neuroplasticity Theory:

• Depression may involve changes in brain plasticity.
• The neurotrophic theory highlights the role of BDNF, a protein that supports neuron growth, survival and differentiation. Depression has been associated with reduced levels of BDNF (Lee et al., 2007), particularly in the hippocampus, an area crucial for memory and emotional regulation (Nestler et al., 2002). Antidepressants and other interventions like exercise are thought to alleviate depression by increasing BDNF levels and thereby enhancing neuroplasticity (Wolkowitz et al., 2011).

HPA Axis Dysregulation / Neuroendocrine

• Elevated cortisol levels observed in the dexamethasone suppression test (DST), where patients with depression show lack of normal cortisol suppression following dexamethasone administration (Asnis et al., 1989)
• Altered HPA axis feedback may lead to chronic stress response contributing to the onset of depressive symptoms due to decreased serotonin function (Porter et al., 2004)

Genetic Influences:

• The gene SLC6A4 encodes the serotonin transporter protein, which is responsible for re-uptaking serotonin from the synaptic cleft back into the presynaptic neuron. Variation in this gene, particularly the 5-HTTLPR polymorphism have been associated with susceptibility to depression, expecially when coupled with stressful life events
• 5-HTTLPR is a degenerate repeat polymorphic region in SLC6A4, the gene that codes for the serotonin transporter.
• One or two copies of the short allele of the 5-HTTLPR polymorphism exhibited more depressive symptoms. (Caspi et al., 2003)

Circadian Rhythm Disruption:

• Abnormalities in sleep patterns, daily rhythms, and hormone cycles are common in depression and may exacerbate other symptoms. Treatments that help normalize these rhythms, such as light therapy and melatonin, can be effective for some patients.

Question 3

Discuss how SSRIs work

Answer 3

Mechanism

SSRIs work by inhibiting the reuptake of serotonin (5-HT) in the brain.

1) Serotonin Release: Serotonin binds to serotonin receptors on the postsynaptic neuron to exert its effect, influencing mood, anxiety and happiness

2) Reuptake Inhibition: SSRIs block serotonin transporter (SERT), reducing the reuptake of serotonin

3) Increased Serotonin Levels: By inhibiting reuptake, SSRIs increase the amount of serotonin available in the synaptic cleft, thereby enhancing serotonergic neurotransmission. This sustained activation of serotonin receptors on the postsynaptic neuron can help alleviate symptoms of depression and anxiety.

Downstream Effects and Adaptations

1) Receptor Sensitivity Adjustments: Chronic exposure to increased serotonin levels leads to various adaptations, such as the downregulation of certain serotonin receptors (like 5-HT2 receptors). These changes help to modulate and normalise serotonergic signalling over time

2) Enhanced Neuroplasticity: SSRIs are believed to enhance neuroplasticity, the ability of the brain to adapt and reorganise itself. This is partly mediated through increased levels of BDNF

3) Normalisation of HPA Axis: SSRIs may help normalise the HPA axis, which is often dysregulated in depression. By reducing the hyperactivity of the HPA axis, SSRIs can decrease excessive cortisol levels, increased serotonin can inhibit CRH (Lenze et al., 2011).

Clinical Implications

• Delayed effect: The antidepressant effects of SSRIs often take several weeks to manifest. This delay is consistent with the time required for neurochemical adaptions and receptor changes to occur in the brain.
• Side effects: Common initial side effects include nausea, headaches and sexual dysfunction (spinal cord sympathetic and parasympathetic neurons), which can be attributed to increased serotonin activity in different parts of the brain and body. Adjusting the dosage or switching to another SSRI can often mitigate these effects. SSRI effects from Raphe projections to hippocampus and limbic cortex = agitation. hypothalamus and in the brainstem (vomiting center of the chemoreceptor trigger zone) = vomiting. Brain stem sleep centre = insomnia. gut wall may mediate the possible gastroinestinal cramps and diarrhea caused by the SSRIs (Stahl, 1998).

Question 4

Discuss how to choose medications for depression

Answer 4

1. Assessment of Depression Severity

• Mild depression might be managed with psychotherapy alone, but if medication is considered necessary, options with a favourable side effect profile such as SSRIs or Bupropion are often preferred
• Moderate to severe depression typically requires pharmacological intervention, and SSRIs are commonly the first line of treatment due to their efficacy and relatively mild side effect profile

2. Patient’s Medical History

• Cardiac disease: Some antidepressants, like tricyclic antidepressants (TCAs), can exacerbate heart conditions due to their cardiac side effects, SSRIs are generally safer in this cohort
• Liver or kidney disease: Medication metabolism might be impaired in these patients, necessitating adjustments in dosages or the selection of medications with safer profiles

3. Psychiatric Histroy

• Previous Response to Antidepressants:
• Family History:

4. Side Effect Profile

• SSRIs are generally well-tolerated but can cause sexual dysfunction, nausea and sleep disturbances (Stahl, 1998)
• TCAs are effective but often limited by more severe side effects such as weight gain, sedation and anticholinergic effects
• MAOIs require dietary restrictions to avoid hypertensive crises and are generally reserved for treatment-resistant cases due to their side effect profile
• Atypical antidepressants like bupropion are useful alternatives, especially in patients who experience sexual dysfunction from SSRIs or those who are trying to quit smoking

5. Interactions with Other Medications

SSRIs can interact with a variety of other drugs through mechanisms like the inhibition of cytochrome P450 enzymes

6. Patient Preferences and Costs

(Cipriani et al., 2018)

Question 5

Describe some non-pharmacological biological treatments for depression

Answer 5

1. Electroconvulsive Therapy (ECT)

• Mechanism: ECT involves inducing controlled seizures by passing small electric currents through the brain under general anaesthesia
• Efficacy: Particularly effective in cases of severe depression, treatment-resistant depression, or depression with psychotic features
• considerations: Potential for transient memory loss and other cognitive effects

(UK ECT Review Group, 2003)

_2. Transcranial Magnetic Stimulation (TMS)

• Mechanism: A coil placed near the head generates brief magnetic pulses, which pass through the skull and stimulate the frontal cortex of the brain, non-invasive stimulation of nerve cells.
• Efficacy: TMS is typically used when other treatments have not been effective and is FDA-approved
• consideration: Does not require sedation, has a few side effects but patent can resume normal activities immediately after treatment.

(Gershon et al., 2003)

3. Vagus Nerve Stimulation (VNS)

• ** Mechanisms:** The device is surgically implanted under the skin of the chest, with a wire that connects to the vagus nerve in the neck which then transmits information to areas of the brain that are believed to regulate mood, sleep and other behaviours
• Efficacy: Considered for long-term treatment of mood disorders in individuals who have not responded to other treatments
• Considerations: Is invasive and carries risks typical of surgical intervention, such as infection or complications from the device

(Austelle et al., 2020)

_4. Deep Brain Stimulation (DBS)

• Mechanism: Implanting electrodes in specific areas of the brain, connected to a generated implant in the chest that sends electrical impulses to the brain.
• Efficacy: For patients with severe, treatment-resistant depression
• Considerations: Due to its invasive nature and potential risks, such as brain haemorrhage or infection, DBS is reserved for those who do not respond to other treatments

(Kisely et al., 2018)

5. Phototherapy/Light Therapy

• Mechanism: Exposure to bright light, particularly in the morning, helps regulate melatonin, improve serotonin levels, and reset the circadian rhythms that influence mood
• Efficacy: Effective for seasonal affective disorder (SAD) and can also help with nonseasonal depression
• Consideration: Non-invasive and can be easily administered at home but requires consistent daily sessions to be effective

(Thalén et al., 2020)