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Current Treatments: Antidepressants

Current Treatments: Antidepressants

By Renee Harvey and Melissa Warner

Antidepressants were first developed around 50 years ago and have now become the most prescribed psychiatric drug.  Around the world, the use of antidepressants has doubled from 2000 to 2015 [i] and continues to rise despite overall effectiveness increasingly being called into question as criticism of research has mounted and limitations and risks have become clearer.  Several subclasses and newer compounds have developed over time as researchers have refined their theories about how they work and attempted to improve their performance.


There are several types, usually described in terms of their theorised mechanism of action[ii].  The broad aim is to influence the balance of neurotransmitters, particularly serotonin, thereby elevating mood.   After the 1950s discovery that serotonin mediated the mood-altering effects of psychedelics in the brain, psychiatry has sought ways to modulate this key network to improve mental health[iii].  The main types of antidepressants are:

Selective serotonin re-uptake inhibitors (SSRIs).
The most prescribed and well-known, these include Prozac and Zoloft.
Selective serotonin and norepinephrine re-uptake inhibitors (SNRIs).
Such as Effexor and Cymbalta.
Monoamine Oxidase Inhibitors (MAOIs)
An older type now used much less frequently because of the dangers of dietary and drug interactions. One example is Amira.
Tricyclic antidepressants (TCAs).
Also an older type of antidepressant, not usually recommended as the first treatment because of more unpleasant side-effects and greater danger if overdosed. Such as Endep.
Atypicals and newly developed compounds have been designed to work on different systems to try to overcome problems and side effects. For example, Zyban and Ketamine.


Australians are the world’s second highest users of antidepressants [iv]; one in eight, or three million Australians are currently on antidepressants [v]. These rates are even high for senior adults, with one in four currently on antidepressants. Despite this vast uptake of use, rates of mental illness continue to rise with a mounting social and economic toll.


Antidepressants held great promise, and many claims for their effectiveness have been made.   The list of side effects for each type is long, often resulting in decreased compliance and discontinuation[i].  Some high-profile instances of death through suicide or violence have sparked great controversy and criticism[ii].  The challenges of suffering depression and lack of better treatment alternatives mean that demand and prescribing continue to rise. The newer antidepressants are reportedly better tolerated and safer.


One of the main challenges in approaching treatment is the long-held belief that antidepressants are at least somewhat effective and have seemed to work better than placebo in various studies.   A meta-analysis found that only 35% of sufferers experience remission from SSRI pharmacotherapy compared to 25% in the placebo group[i].  Findings have suggested that various forms of psychotherapy are equally if not more effective[ii], but because of lack of availability, long duration and high cost[iii], medication remains the only option for most people.  However, another  recent large review of research[iv] seemed to support that antidepressants were superior over placebo, but in criticism of this a further review[v] has pointed to serious flaws in methodology, biased reporting and modest effect sizes at best, concluding that antidepressants many be no more effective than placebo.  Frequently, there is high participant drop-off in the active group and studies fail to differentiate between remission and clinical response (a reduction in symptoms). A prolific population study, the STAR*D trail, found that anti-depressants led to remission from depression in only 3% of the over 4000 participants surveyed[vi].


To address the escalating need, effective and holistic treatment options are required for mental illness. Novel approaches may include the integration of therapeutic practice with medicines, such as psilocybin and MDMA, that catalyse the therapeutic environment. The antidepressant effects of ketamine were discovered about twenty years ago, and this is being researched as a novel treatment.  The future of this, as well as outcomes of research with psychedelic-assisted therapy may point to a different future for people with depression. The development of medicine-assisted therapy alongside evidence-based lifestyle change may allow practitioners to address the underlining biochemical, experiential and environmental factors of mental illness.


Recent research suggests the role of serotonin in the brain is far more complex than previously thought. Dr Robin Carhart Harris, head of Imperial College’s Centre for Psychedelic Research delineates two pathways within the brain’s serotonin system. Carhart-Harris suggest that “we have a system that helps us get by, and a system for no longer just getting by but for creating a substantial change”[i]. SSRI’s may benefit some patients but most relapse when daily dosing stops[ii]. This maybe because SSRI’s activate a part of the serotonin system associated with moderating emotion and promoting patience, but not creating change [iii].

This mechanism contrasts with how psychedelic medicines appear to work in the brain. Whereas SSRIs may “mitigate stress, stop the bottom from falling out and help you get by… psychedelics are not about getting by but about transformation” vi says Dr Carhart-Harris. Psychedelic medicines activate the serotonin 5HT2a receptors which mediate a signalling system associated with strategy change viii.  Serotonin 5HT2a receptors increase in number within the brain under conditions of high stress, such as sleep deprivation and hypoxia (a lack of oxygen)[iv] and may evoke an adaptive response akin to a ‘healing crisis’[v].   Recent research suggests that the 5HT2a receptor aids adaptivity through enhancing sensitivity to context, learning and unlearning, cognitive flexibility and synaptogenesis (new neuronal connections)[vi].

While SSRI’s may temporarily make life more tolerable, psychedelic-assisted therapy appears to work by enhancing a patient’s capacity for change, aiding them to ‘pivot’ and shift into a revised way of being.


[1] Health at a Glance 2017: OECD Indicators: Antidepressant drugs consumption, 2000 and 2015 (or nearest year)


[1] Hillhouse, T.M. & Porter, J.H. (2017). A brief history of the development of antidepressant drugs:  from monoamines to glutamate. Exp Clin Psychopharmacol. 2015 February ; 23(1): 1–21.

[1] Whitaker-Azmitia, P. The Discovery of Serotonin and its Role in Neuroscience. Neuropsychopharmacol 21, 2–8 (1999) doi:10.1016/S0893-133X(99)00031-7

[1] Department of Human Services. (2019). Table 1 – Number and % of Australian patients (by age group) prescribed an antidepressant from 2012-13 to 2017-18. Data published by Psych Watch Australia in 1 in 8 (over 3 million) Australians are on antidepressants – Why is the Lucky Country so miserable? (2019).

[1] Kwawam, E.A. et al. (2006).  Side effects of antidepressants: An overview. Cleveland Clinic Journal of Medicine, 73:4, 351-361.

[1] Moore, A. (2007). Eternal Sunshine, available online.

[1] Thase ME, Entsuah AR, Rudolph RI. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry. 2001;178:234–41

[1] Cuijpers, P. (2013). A meta-analysis of Cognitive-Behavioural Therapy for adult depression, alone and in comparison with other treatments. CanJPsychiatry 2013;58(7):376–385

[1] Orygen Youth Health Research Centre. (2014). Work, Education and Young People with Mental Health in Australia: Tell Them They’re Dreaming. Policy Impliocations. Pg 14.

[1] Cipriani, A. (2018). Comparative efficacy and acceptability of 21 anti-depressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis.  Lancet, 391: 1357-66.

[1] Munkholm, K., Paludan-Müller, A.S. & Boesen, K. (2019). BMJ Open 2019;9:e024886. doi:10.1136/bmjopen-2018-024886

[1] Pigott H E. (2015). The STAR*D Trial: It Is Time to Re-examine the Clinical Beliefs That Guide the Treatment of Major Depression. Can J Psychiatry. 60(1): 9–13.

[1] Dr Robin Carhart-Harris – A Unified Model of the Brain Action of Psychedelics. Breaking Convention 2019

[1] Mueller, T. I., Leon, A. C., Keller, M. B., Solomon, D. A., Endicott, J., Coryell, W., . . . Maser, J. D. (1999). Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. American Journal of Psychiatry, 156(7), 1000-1006.

[1] Carhart-Harris R. L. (2018). Serotonin, psychedelics and psychiatry. World psychiatry: official journal of the World Psychiatric Association (WPA), 17(3), 358–359. doi:10.1002/wps.20555

[1] Moya & Powell. (2016).  Effects of A2A and 5-HT2A Antagonists on Hypoxic and Hypercapnic Ventilatory Response in Rats Exposed to Chronic Sustained Hypoxia. Federation of American Societies for Experimental Biology. 30(1).

[1] Maple et al.  (2015). Htr2a expression responds rapidly to environmental stimuli in an Egr3-dependent manner. ACS chemical neuroscience, 6(7), 1137-1142.

[1] Carhart-Harris, R. L., & Nutt, D. J. (2017). Serotonin and brain function: a tale of two receptors. Journal of Psychopharmacology, 31(9), 1091-1120.

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