Depression is one of the most debilitating psychiatric disorders, affecting 20% of the population1. According to the World Health Organization, as of 30 January 2020 over 264 million people of all ages were suffering from depression worldwide2. People with depression suffer a range of emotional, cognitive, physical, and behavioural alterations including sadness, anxiety, guilt, irritability, impaired memory, thoughts of death and suicide, loss of motivation, disturbed sleep or appetite, tiredness, neglect of responsibilities, changes in personal appearance, and withdrawal from others3. Depressive disorders lead to a substantial reduction in quality of life, as well as disruptions in work/school performance, family/social life, and common daily activities2, 3.
The cause of major depressive disorder is multifactorial with genetic and environmental factors playing a role, and although hereditary factors increase risk, depression can occur in people without family histories of depression4. Other identified risk factors include neurodegenerative diseases (especially Alzheimer’s disease and Parkinson’s disease), stroke, multiple sclerosis, seizure disorders, cancer, macular degeneration, and chronic pain. Adverse life events can operate as triggers for the development of depression and include the loss of a loved one, lack of or reduced social support, caregiver burden, unemployment, financial problems, and interpersonal difficulties and conflicts2, 4.
Neurotransmitters and depression
It is still unclear what biological mechanisms are involved in the development of depression. Current evidence points to a complex interaction between neurotransmitter availability, regulation, and sensitivity. Clinical and preclinical trials suggest a key role in the disturbance in central nervous system serotonin (5-HT) activity. Other neurotransmitters implicated include norepinephrine (NE), dopamine (DA), glutamate, and brain-derived neurotrophic factor (BDNF)4.
Standard therapies for depression
The most common treatments include behavioural activation, cognitive behavioural therapy (CBT), or interpersonal psychotherapy (IPT). This can be used alone or in combination with antidepressants such as selective serotonin uptake inhibitors (SSRIs), serotonin/norepinephrine reuptake inhibitors (SNRIs), serotonin-dopamine activity modulators (SDAMs), monoamine oxidase inhibitors (MAOIs), or tricyclic antidepressants (TCAs). Antidepressants are the first-line treatment prescribed for depression in adults; however, not all patients achieve full remission, and approximately 30% are unresponsive5. Consequently, depression tends to be chronic with high rates of recurrence and relapse6.
New and potential therapies for depression
Esketamine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist and was approved in 2020 in the USA as a rapid-acting, short-term therapy for severe depression in adults, specifically those experiencing suicidal thoughts and in whom all other treatments have failed. Esketamine targets not one but a number of brain connections at the same time and builds new synapses and increases the levels of the neurotransmitter glutamate, which many neurons in the brain use to communicate with each other. Esketamine is administered in conjunction with other antidepressants and its safety and efficacy have been shown in randomised, placebo controlled clinical trials, albeit with limitations, in that it seems to be most effective in younger people7-10.
Pimavanserin is an antipsychotic drug that regulates serotonin neurotransmission by selectively binding to two specific serotonin receptor subtypes. It may have potential as an adjunctive treatment for major depressive disorder. In a clinical study with 203 patients, addition of pimavanserin to standard treatment with antidepressants significantly reduced symptoms of depression, specifically impaired sexual function, anxiety, sleepiness, and irritability, compared to placebo. Clinical trials are still in progress to clarify the utility of adjunctive pimavanserin in the treatment of patients with major depressive disorder11.
Cannabinoids. In recent years, clinical and preclinical evidence has shown a link between defects in the endocannabinoid system (ECS) and depression12-14. The ECS controls the crosstalk between different neurotransmitter systems by signaling through endocannabinoids (cannabinoids produced naturally in the body). These endocannabinoids bind to and regulate the activity of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors in the central nervous system. This signaling plays a key role in the control of emotions and behavioural responses such as fear, anxiety, depression, stress-coping, and reward-driven behaviour15, 16. CB1 receptors are expressed in the limbic and frontal regions of the brain which are involved in the control of mood and behaviour and regulate serotonin transmission17, 18. Studies using animal models of depression have shown that reducing ECS activity induces depressive-like behaviours in the animals19-22, and patients with major depression have reduced circulating levels of endocannabinoids13, 23. Thus, it has been proposed that enhancing ECS signalling with plant cannabinoids may exert antidepressant effects24, 25.
Interestingly, studies have shown that the clinical effect of some antidepressants is mediated by the modulation of ECS activity in specific brain regions, including the hypothalamus, the amygdala, and the hippocampus. Chronic treatment with TCAs increases the number of CB1 receptors in the hippocampus and hypothalamus and reduces hypothalamic-pituitary-adrenal (HPA) axis activation in response to stressing stimuli23, 26.
In animal studies, the non-psychoactive plant cannabinoid, cannabidiol (CBD), has been shown to interact with multiple neurotransmitter systems involved in depression, including the serotonergic, glutamatergic, and ECS systems. Moreover, CBD induces cellular and molecular changes in brain regions related to depression neurobiology, such as increased BDNF levels and the generation of new neurons and synapses in the medial prefrontal cortex and in the hippocampus27-30. In these studies, administration of CBD either alone or in conjunction with antidepressants, minimised anxiety, depression, and stress-related behaviours31.
In humans, there are a few studies showing the beneficial effects of medicinal cannabis on depression as a primary or secondary outcome32, 33. For example, a study in cancer patients using a formulation with CBD and tetrahydrocannabinol (THC), the psychoactive plant cannabinoid, showed a significant reduction in mood for those who used the highest dose compared to placebo34. On the other hand, there are also several studies showing no measurable effect35-39. Three studies assessing the same CBD-THC formulation above for multiple sclerosis and cannabis withdrawal found no significant effect on the secondary outcome of depression40-42. Some epidemiological studies have found a greater level of depressive symptoms in heavy recreational cannabis (i.e. containing high levels of THC) users compared to light-users and nonusers43. Due to this, it is recommended that higher doses of medicinal THC should be avoided in people with major depressive disorder44.
It is clear that more good quality data is needed. A currently recruiting double-blind, randomised, placebo-controlled clinical trial (NCT03310593) is evaluating the safety and efficacy of CBD in reducing anxiety and depression in 100 participants with bipolar disorder and is due for completion in 2022. In Australia, two large observational trials (ACTRN12621000063819 and ACTRN12620000741987) in 2142 and 500 participants, respectively, are evaluating safety and patient-reported quality of life outcomes, including changes in depression, in people with chronic conditions being prescribed medicinal cannabis, and are due for completion in 2022/2023. Thus, the clinical efficacy and safety of cannabinoids for the treatment of depression will continue to be debated until new data emerges from these current studies and future large scale, blinded, controlled clinical trials45, 46.
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- Hardeveld F, Spijker J, De Graaf R, Hendriks SM, Licht CM, Nolen WA, et al. Recurrence of major depressive disorder across different treatment settings: results from the NESDA study. J Affect Disord. 2013;147(1-3):225-31.
- Daly EJ, Singh JB, Fedgchin M, Cooper K, Lim P, Shelton RC, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75(2):139-48.
- Fedgchin M, Trivedi M, Daly EJ, Melkote R, Lane R, Lim P, et al. Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1). Int J Neuropsychopharmacol. 2019;22(10):616-30.
- Ochs-Ross R, Daly EJ, Zhang Y, Lane R, Lim P, Morrison RL, et al. Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3. Am J Geriatr Psychiatry. 2020;28(2):121-41.
- Popova V, Daly EJ, Trivedi M, Cooper K, Lane R, Lim P, et al. Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Am J Psychiatry. 2019;176(6):428-38.
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