Treatments for Major Depressive Disorder

Image showing the difference between the
brain of a Depressed and Non-depressed individual
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This image shows that Depression is a biological brain disorder.
Image A shows the brain of a depressed individual
whereas image B shows a non-depressed individual's brain.
Both the brains differ in the level and location of brain activation.
Image source:

According to DSM IV-TR, Major Depressive Disorder is defined as a significant decrease in pleasure for otherwise pleasurable activities and/or a depressed mood for a time period of at least 14 days that negatively affects the social, work and/or family life of the affected person, on a daily basis[1]. Depression is one of the three most common psychological disorders with a lifetime prevalence of 16% in the U.S[2]. Moreover, between 1/3 to 2/3 of patients do not respond to the first line of treatment as outlined by the American Psychiatric Association [3].

As depression is a widespread disorder among the population, various approaches are currently used and continuously explored to optimally reduce its severity. A first standard for treating major depressive disorder (MDD) turns out to be antidepressant medication, such as serotonin reuptake inhibitors (SSRIs)[4]. Antidepressants are often used to restore the neurobiological changes (structural, functional and molecular) that occur in several areas of the brain and therefore are more relevant to the neurobiology of Major Depression than other treatments[4]. For instance, SSRIs have shown to alter behaviour through attenuating amygdala activity[5]. More often than not, psychotherapy is assigned in conjunction with treatment to tackle both top-down and bottom-up aspects of the disorder- exploring both the psychological as well as the neurobiological side by altering thoughts and behaviors, and at the same time changing brain activity and altering structural composition[6]. Exercise has been recognized to induce antidepressant effects[7]. Other forms of non-invasive as well as invasive treatments, such as repetitive transcranial magnetic stimulation (rTMS), electroconvulsive treatment (ECT) and deep brain stimulation (DBS) tackle direct brain regions when first line approaches are ineffective. The clinical use of different types of treatments shows that there is a lot of variability in the degree to which this disorder manifests itself in people and in the responsiveness of patients to any given treatment.

1. Managing Depressive Symptoms in Substance Abuse Clients During Early Recovery Treatment Improvement Protocol (TIP) Series, No. 48. Appendix D - DSM - IV -TR Mood Disorders. Center for substance abuse treatment.Rockville (MD): Substance abuse and mental health services administration (US). (2008). Available from:
2. McKnight, PE & Kashdan, TB.The importance of functional impairment to mental health outcomes: a case for reassessing our goals in depression treatment research. Clin Psychol Rev. (2009) 29(3): 243-259
3. Carek, PJ, Laibstain SE, Carek SM. Exercise for the treatment of depression and anxiety. Int J Psychiatry Med. (2011) 41(1): 15-28
4. Maletic, V. et al. Neurobiology of Depression: an integrated view of key findings. Int J Clin Pract. (2007) 61(12): 2030-2040
5. Ruhe, HG. et al. Occupancy of serotonin transporters in the amygdala by paroxetine in association with attenuation of left amygdala activation by negative faces in major depressive disorder. Psychiatry Research: Neuroimaging (2013)
6. Lynch, FL. et al. Incremental cost-effectiveness of combined therapy vs medication only for youth with selective serotonin reuptake inhibitor-resistant depression: Treatment of SSRI-resistant depression in adolescents trial findings. Archives of General Psychiatry. (2011) 68(3): 253-262
7. Ernst et al. Antidepressant effects on exercise: Evidence for an adult-neurogenesis hypothesis. Rev Psychiatr Neurosci. (2007) 31(2): 84-89.

Deep Brain Stimulation (DBS)

main article: Deep Brain Stimulation (DBS)
author: Vinoja Sebanayagam

Localization of DBS electrodes
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Post operative X ray image showing the location of DBS electrodes
(indicated by arrows) in the patient’s cranium. Image source: Sclaepfer, TE et al, 2008 [5]

Deep Brain stimulation (DBS) is a new technique that is being considered an effective line of treatment for people suffering from severe depression. This intervention is thought to be particularly effective for a third of the total number of patients who seem to be having a relatively poor prognosis than others and are considered to be suffering from Treatment Resistant Depression (TRD) [1].TRD patients fail to respond to adequate courses of at least two different anti depressant medications[2]

Deep Brain stimulation is currently being thought to be useful in stimulating certain anatomical structures of the brain that are implicated in Major Depression. These structures include: The Subgenual Cingulate (Brodmann Area 25), Nucleus Accumbens and Anterior Limb of the Internal Capsule (ALIC) [1]. Moreover, new evidence suggests that the Lateral Habenula[1], the Medial Forebrain Bundle[1] and Ventral Striatum[3] also might serve as potential targets for stimulation and there are clinical trials being conducted at present to confirm this. Another interesting observation that has been made with respect to these brain structures is that some are seen to be overactive (eg: ALIC, Lateral Habenula and Area 25) while others are underactive (eg: Nucleus Accumbens) and these observations are mostly consistent with some of the symptoms seen in depressed individuals[1].

The Food and Drug Administration (FDA) has not yet approved DBS as a treatment strategy that can be used to clinically treat patients because of certain limitations that are evident from clinical trials - including variability in positive responses from patients[4], small sample sizes in research studies[4] and other side effects of DBS including suicidal tendencies & agitation observed among patients and possible wound infections[1].

1. Schlaepfer, TE & Bewernick, BH. Deep Brain Stimulation for Major Depression. Hand Clin Neurol. (2013). 116 (3): 235-243
2. Wijeratne, C & Sachdev, P. Treatment-resistant Depression: critique of current approaches. Aust N Z J Psychiatry. (2008). 42(9): 751-762
3. Taghva, AS, Malone, DA & Rezai, AR. Deep Brain Stimulation for Treatment Resistant Depression. World Neurosurg. (2013). 80(3/4): S27.e17 – S27.e24 (ePub)
4. Lakhan, SE & Callaway, E. Deep Brain Stimulation for Obsessive Compulsory Disorder and Treatment Resistant Depression: systematic review. BMC Research Notes. (2010). 3: 60
5. Sclaepfer, TE et al. Deep Brain Stimulation to reward circuitry alleviates anhedonia in refractory major depression. Neuropsychopharmacology. (2008). 33: 368-377


main article: Psychotherapy
author: Cherie Kong

Psychotherapy for MDD
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Psychotherapy as one of the effective treatments for MDD

Psychotherapy is one of the most common treatments for Major Depressive Disorder (MDD) together with antidepressants. It is the best option for mild to moderate depression, or combines with medication to treat severe depression, and is the most successful way to prevent relapse of the disorder[1]. Psychotherapy employs psychological therapeutic techniques to eliminate the depressive symptoms and behaviors of patients. Cognitive behavioral therapy (CBT) is the main and most effective type of psychotherapy to treat depression, which helps clients to address negative thoughts and problems, learn to positively interpret the environment and change their behaviors[1]. Studies have shown that the psychological and behavioral changes after CBT are associated with neurobiological changes in the prefrontal-limbic pathway, such as decreased metabolic activities in the oribitofrontal cortex and the medial prefrontal cortex[2]. More recent findings indicated a consistent result of neurological changes after CBT, and it is shown to be a normalization of brain activity, particularly when the brain is processing negative emotional stimuli[3].

In addition to CBT, other studies also found some structural changes as well as increases of serotonin binding sites in the cortical region after other forms of psychotherapy, such as the psychodynamic therapy[4]. Psychotherapy is designed to help depressed patients to understand and restructure their emotions, thoughts and behaviors, and more importantly, to improve coping strategies and problem solving skills [1]. The prefrontal-limbic regions are responsible for these functions, therefore, the structural and functional changes in these particular brain regions, induced by psychotherapy, explained the effectiveness of psychotherapy[2]. More future findings in neurobiological changes after psychotherapy will enhance the understanding of how psychotherapy works biologically and benefit in designing a more effective psychotherapy to target specific brain areas[5].

1. Depression. National Institution of Mental Health (NIMH). (2011). Available from
2. Goldapple, K. et al. Modulation of cortical–limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch. Gen. Psychiatry. (2004) 61(1): 34–41
3. Yoshimura, S. et al. Cognitive behavioral therapy for depression changes medial prefrontal and ventral anterior cingulate cortex activity associated with self-referential processing. Soc Cogn Affect Neurosci. (2013). 10.1093/scan/nst009
4. Karlsson, H. et al. Research letter: psychotherapy increases brain serotonin 5-HT1A receptors in patients with major depressive disorder. Psychol. Med. (2010) 40(3): 523–528
5. Lynch, FL. et al. Incremental cost-effectiveness of combined therapy vs medication only for youth with selective serotonin reuptake inhibitor-resistant depression: treatment of SSRI-resistant depression in adolescents trial findings. Archives of General Psychiatry. (2011) 68(3): 253-262

repetitive Transcranial Magnetic Stimulation (rTMS)

main article: repetitive Transcranial Magnetic Stimulation (rTMS)
author: Saba Shahab

rTMS equipment and positioning
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Image source:

Only around 33% of patients with Major Depressive Disorder respond to antidepressants such as SSRIs, and research shows that this rate of remission (optimal recovery after treatment) doesn’t change even when a combination of antidepressants are used[1]. Alternative treatments for treatment-resistant depression (TRD) are thus important and include Electroconvulsive Therapy (ECT), Deep Brain Stimulation (DBS) and repetitive Transcranial Magnetic Stimulation (rTMS).

rTMS takes advantage of magnetic waves created by an electrical coil to induce a current in neurons to modify neuronal excitability[2]. Structures usually targeted in patients with depression include the dorsolateral prefrontal cortex (DLPFC) and the dorsomedial prefrontal cortex (DMPFC)[3]. The DMPFC is involved in controlling the interaction of brain networks involved in rumination (Task-Negative Network), somatic markers for physiological states (Somatic Marker Network) and goal-directed behaviour (Task-Positive Network)[3]. DLPFC is a part of the Task-Positive Network. Both DLPFC and DMPFC have decreased activity in depressed patients and are treated by rTMS to increase their neuronal activity[3].

Side-effects associated with rTMS are milder and better known than some other treatments for TRD. For instance, ECT is known to cause temporary retrograde amnesia[4] and the side effects of DBS are still controversial which is why DBS is only a potential treatment for TRD and has not yet been used clinically[5]. Severe side-effects associated with rTMS are very rare and include seizures and increased chances of mania[6]. However, more common rTMS side-effects are only temporary headaches that are mild to moderate in nature and are usually tolerable by patients[6]. It is for these reasons that rTMS, which first emerged in the 1980s[7], is gaining popularity over time as a treatment for TRD and also as an adjunct therapy with antidepressants.

1. Stewart, J. W., et al. Combination Antidepressant Therapy for Major Depressive Disorder: Speed and Probability of Remission. Journal of Psychiatric Research. (2013).
2. Health Quality Ontario. Repetitive transcranial magnetic stimulation for the treatment of major depressive disorder: an evidence-based analysis. Ontario health technology assessment series. (2004).4(7),1.
3. Downar, J., & Daskalakis, Z. J. New targets for rTMS in depression: a review of convergent evidence. Brain stimulation. (2013). 6(3), 231-240.
4. Meeter, M., Murre, J. M., Janssen, S. M., Birkenhager, T., & van Den Broek, W. W. Retrograde amnesia after electroconvulsive therapy: A temporary effect?. Journal of affective disorders. (2011). 132(1), 216-222.
5. Pinsker, M., Amtage, F., Berger, M., Nikkhah, G., & van Elst, L. T. Psychiatric Side-Effects of Bilateral Deep Brain Stimulation for Movement Disorders. In Stereotactic and Functional Neurosurgery. Springer Vienna. (2013). 47-51.
6. Fitzgerald, P. B., & Daskalakis, Z. J. Side Effects of rTMS Treatment. In Repetitive Transcranial Magnetic Stimulation Treatment for Depressive Disorders. Springer Berlin Heidelberg. (2013). 7-12.
7. Fitzgerald, P. B., & Daskalakis, Z. J. The History of TMS and rTMS Treatment of Depression. In Repetitive Transcranial Magnetic Stimulation Treatment for Depressive Disorders. Springer Berlin Heidelberg. (2013). 7-12.


main article: SSRIs
author: Dorothy Choi

Mechanism of Serotonin
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SSRIs reduces serotonin reuptake. Image Source:

Serotonin Reuptake Inhibitors (SSRIs) are generally the first line of treatment for major depression, anxiety, and other personality disorders as well. They are a form of antidepressants that act to increase the levels of extracellular serotonin (5-HT) in the synaptic cleft, by inhibiting its reuptake [1]. This process occurs by the conjunction of SSRIs and serotonin transporter (5-HTT or SERT), preventing serotonin from being transported back into the pre-synaptic cleft. In consequence, more serotonin is produced, as the negative feedback mechanism of serotonin-SERT reuptake is withdrawn [1].

In return, the activity of the amygdala is less sensitive towards negative stimuli [2], as well as reduced hyper-stimulation of other brain regions [2].
On the other hand, whether SSRIs are suitable for the elderly age group is debated [3], and its correlation with higher suicide tendencies versus suicide protection is variable [3].
SSRIs help to provide a better neurochemical balance that provides similar learning experiences, relative to healthy subjects [1]. Although similar, the brain system of major depression subjects is not normal like healthy subjects [1].

1. Herzallah et al. Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants. Frontiers in Integrative Neuroscience.(2013) 67 (7): 1-9
2. Ruhe, HG. et al. Occupancy of serotonin transporters in the amygdala by paroxetine in association with attenuation of left amygdala activation by negative faces in major depressive disorder. Psychiatry Research: Neuroimaging (2013)
3. Topiwala A, et al. Prescribing selective serotonin reuptake inhibitors in older age. Maturitas (2013)

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