A Report On The Pharmacological Treatment Of Depression
Introduction
Depression is the most common affective (mood) disorder, it has a range of severities and is a major cause of disability and premature deaths. There is also significant comorbidity associated with depression, increasing risk of many other diseases, such as cardiovascular diseases alongside it (possibly stress related).
Depression is likely a range of distinct neurological causes that are grouped together under an umbrella term for the symptoms that individuals exhibit. It is especially prevalent in high income countries however the mechanism behind it has not been well characterised. Depression is often idiopathic, with no obvious cause. In some cases, there is a familial pattern, family and twin studies have shown that major depressive disorder is familial in nature however no specific genes have been identified as a possible cause, it is likely more complex, involving environmental factors and numerous genes. Historically, the prevailing theory of depression has been based upon the effectiveness of pharmacological intervention. This has lead to a focus on monoamines and their role as neurotransmitters within the brain. It has been shown that lowered serotonin and noradrenaline pathway activity cam produce depressive symptoms. The monoaminergic pathways are largely located in the brainstem (such as 5-HT and NA from the locus coeruleus and dopamine from the substantia nigra) and exhibit modulatory effects, projecting to large areas across the brain. This implicates them in a range of functions such as mood, attention, sleep, and cognition. Making them a plausible candidate in the pathogenesis of depression. Further to this, reserpine is an irreversible blocker of vesicular monoamine transporter (VMAT) which leads to decreased monoamine release as more is degraded and less enters vesicles for release. Reserpine has been shown to induce depression in a subset of patients that took it as an antihypertensive agent.
These factors initially highlighted monoamines as a likely candidate for a cause of depression, by looking at pharmacological treatment of depression I will highlight the support for this theory and also look at other possible theories that imply lowered monoamine levels are not a direct cause of depression.
Monoamine Reuptake Inhibitors
Selective Serotonin Reuptake Inhibitors – SSRI’s
This class of drugs are the most commonly prescribed antidepressants such as sertraline, fluoxetine, and paroxetine. They are selective for reuptake of 5-HT, inhibiting the 5-HT transporter that pumps serotonin back into the presynaptic neuron. This has the effect of increasing the concentration of 5-HT at a synapse which therefore will increase binding of 5-HT to receptors post-synaptically, perpetuating their normal physiological effects. The antidepressive actions of SSRI’s are not seen as quickly as changes at the nerve terminal, which could imply that secondary actions of these drugs are contributing to their therapeutic effects. In actuality, there is a smaller increase in 5-HT at the nerve terminal than would be expected. This is due to the effects of 5-HT on raphe neurons which themselves contain 5-HT. Serotonin activates 5-HT1A receptors on the soma and dendrites of these neurons, inhibiting them and subsequently reducing release of 5-HT. This effect is eventually overcome on chronic administration of SSRI’s as the 5-HT1A receptor becomes desensitised and the inhibitory effect is lost. This process can account for the delayed action of SSRI’s to increase 5-HT and why antidepressive effects are not seen as quickly as neurochemical changes are. The effectiveness of these drugs in treatment of depression supports the monoamine hypothesis as it implies that one of the underlying causes or factors in depression is lower levels of 5-HT, which are reversed by an increase in 5-HT levels by inhibiting reuptake chronically.
Tricyclic Antidepressant Drugs – TCA’s
TCA’s are more classical drugs used to treat depression, their use has dropped in favour of safer more targeted drugs. They have more serious side effects than SSRI’s and more acute toxicity whilst having a similar efficacy and speed of action. Examples of this class of drugs are amitriptyline and imipramine. Similarly, to SSRI’s they block 5-HT reuptake, they are non-selective monoamine reuptake inhibitors however and so also inhibit reuptake of noradrenaline and to a smaller degree, dopamine. The action of TCA’s varies greatly between different types and are non-selective, also having inhibitory actions at H1 receptors, α-adrenoreceptors and muscarinic ACh receptors and the various metabolites of TCA’s have pharmacological effects. This produces a range of side effects such as sedation, postural hypotension, and constipation with some risk of ventricular dysrhythmias. TCA’s are also used in many other mood disorders as well as against neuropathic pain. The antidepressive effects of these drugs has also been attributed to raising levels of 5-HT and NA again implicating that there is a deficiency of monoamines in affected individuals.
Serotonin and Noradrenaline Reuptake Inhibitors – SNRI’s
These are fairly similar to TCA’s except that they have a reduced toxicity and side effects, examples are venlafaxine and duloxetine. They are fairly weak non-selective NA/5-HT reuptake inhibitors and have been claimed to have both higher efficacy than other drugs and more success in patients that are drug-resistant. Again, these drugs support a theory of monoamine involvement in depression as they raise the levels of these neurotransmitters.
Monoamine Receptor Antagonists
An example of this class of drugs is mirtazapine, it is an α2 adrenoreceptor antagonist but also affects the 5-HT2c receptor. The effects of antagonising α2 receptors is that it will enhance release of NA and consequently 5-HT also. 5-HT release is stimulated by binding of NA to α1 adrenoreceptors post-synaptically, release of NA is inhibited by activation of α2 adrenoreceptors presynaptically and therefore will reduce release of 5-HT. Antagonising the α2 receptor will reverse this inhibitory effect and lead to increased release and 5-HT mediated effects. The effectiveness of this drug class in treatment of depression also lends support to the theory of reduced monoamine levels being involved in the pathogenesis of depression.
Monoamine Oxidase Inhibitors
This class of drugs acts at the enzyme monoamine oxidase which is involved the breakdown and therefore inactivation of monoamines. MAO-A has a higher affinity for 5-HT whereas MAO-B has higher affinity for dopamine and is therefore targeted more in the treatment of Parkinson’s disease. In mice, if the MAO-A gene (separate gene to MAO-B) is disrupted, then there is an increase in 5-HT levels within the brain as well as some increase in NA as well as a more aggressive behaviour observed. Due to MAO-A having a greater effect on 5-HT, it is the target in treatment of depression however the drugs used most often act at both subtypes. Example drugs are phenelzine and iproniazid. Usually MAO will regulate the concentration of monoamines within nerve terminals, it has no effect on released neurotransmitter. Inhibitors exhibit a rapid increase in levels of monoamines. This leads to increased cytoplasmic concentration of monoamines within nerve terminals as less is broken down, this can actually result in increased spontaneous monoamine leakage which can have unwanted side effects such as acute hypertension on ingestion of tyramine, which is now not broken down by MAO in the gut and can have serious effects such as intracranial haemorrhage due to a displacement of endogenous monoamines. This is known as the ‘cheese reaction’ due to the presence of tyramine in fermented foods. The effect of MAOI’s is rapid biochemically but again the antidepressive effects are not seen as quickly again, with no clear mechanism t account for this. This seems to indicate that there is likely a secondary action of monoamines that is accounting for the antidepressive effects. This could once more be due to receptor desensitisation effects or other signalling pathways downstream of the monoamines.
Future Pharmacological Interventions
Ketamine
Despite the main drugs used to treat depression focussing on the monoamine system, there is lots of evidence to suggest that it is not reduced levels of these neurotransmitters alone that cause depressive symptoms, evidence for this is the fact that by decreasing the availability of tryptophan (precursor necessary for 5-HT production) in healthy individuals using a tryptophan-free amino acid mixture, no significant change in mood is observed and depression is not induced. One such piece of evidence is the effectiveness of an IV administration of a subanaesthetic dose of ketamine to acutely alleviate depression. Ketamine is an NMDA receptor antagonist which occupies the ion channel of this glutamatergic receptor.
NMDA receptors produce long-term potentiation, inhibition of which in the hippocampus has been linked to stress response within rodents. The precise mechanism by which ketamine can treat depression is unknown however studies in animals has indicated that ketamine facilitates synaptogenesis, implicating neurogenesis as an anti-depressive process and therefore neural apoptosis with depression. NMDA receptor blockade may increase glutamate release due to reduced activity of GABAergic neurons that would usually be activated by the NMDA receptors, this leads to overall increased activation of AMPA receptors glutamatergically which may produce the therapeutic effect.
CRF Receptor Antagonists
The hypothalamic-pituitary axis has also been implicated in the mechanisms behind depression. Patients often display hypersecretion of cortisol alongside depression, increased levels of corticotrophin-releasing factor (CRF) within the CSF is also observed. Disruption of the HPA within Cushing’s disease also creates mood changes (depressed state) which is resolved by reducing cortisol levels. Injection of CRH into the brains of animals have shown changes associated with depression in humans, periods of stress also often occur before depression manifests in many cases. Antagonistic drugs acting at the receptor for CRH have shown initial promise in clinical trials to successfully reduce depressive scores without detrimentally affecting the HPA in the context of hormone release.
Neurogenesis
It has been hypothesised that neuronal loss within the hippocampus and prefrontal cortex may be a cause of depression and therefore reversal of this via neurogenesis and reduced neuronal loss may be a common route of antidepressants action. Low levels of brain-derived neurotrophic factor (BDNF) and decreased activity of its receptor (TrkB) have also been implicated in depression, implying reduced neurogenesis could be a factor. TCA’s may play a role in modulating glucocorticoid actions (at an mRNA level) which themselves regulate neurogenesis and hippocampal size. The precise mechanisms by which monoamines may intracellularly produce signalling cascades to induce neurogenesis are not currently known, though some may be revealed in the future. The figure below highlights possible interactions between the numerous pathways described and how they could theoretically contribute to depression.
Conclusion
Despite large pieces of pharmacological evidence highlighting monoamines as a causal agent for depression when at low levels, it is more likely that these low levels are a secondary messaging factor in the pathogenesis of depression and can be targeted to restore some balance. Evidence now suggests that neurogenesis in specific regions of the brain and the balance with neural apoptosis is particularly important. This fits well with the idea that antidepressants take time to show positive effects, implying more chronic trophic actions. As well as neurogenesis, chronic stress pathways such as the HPA are involved to some degree, highlighted by CRH receptor antagonist effectiveness. The role of NMDA receptor antagonists in synaptogenesis is also promising and targeting of this pathway could give way to potential future treatments as it appears as a more direct effector of neuronal changes than the monoamine mediated systems, highlighted by the swift action of ketamine to acutely treat depression. These pathways and mechanisms are likely to interact with eACh other, when out of balance, this could lead to the manifestation of depressive symptoms. Interestingly, different individuals respond to different medications very differently, this may imply that there are numerous different forms of depression that involve different mechanisms, if the classification and understanding of depression was improved, higher specificity targeting of different mechanisms pharmacologically could improve outcomes greatly. Currently however, due to animal models that are not always indicative of human mood disorders and a difficulty in characterising depression, this is not possible.
