Author:
Alan Woodruff

Key points

  • Treatments produce lasting remission in only 30–50% of patients.
  • Current treatments include SSRIs, psychotherapy, and electroconvulsive shock therapy.
  • Future treatments are likely to include new pharmacological agents, such as ketamine, and alternative electrical brain stimulation paradigms, such as DBS.

In an earlier article, some of the biology underlying depression was explained. The disorder, which is often caused by high stress levels, is characterised by a misalignment in how a person interprets positive and negative information: positive, rewarding events are underemphasised while the opposite is true for negative events. Specific brain structures and neurotransmitters are involved in these changes. Here, a brief rundown on current and future treatments is provided.

Current treatments

Various approaches have been used to alleviate the symptoms of depression, including cognitive behavioural therapy (CBT), drugs and electroconvulsive therapy (ECT).

Cognitive Behavioural Therapy

As mentioned above and covered in another article, depressed patients display negative emotional bias and have difficulty deriving pleasure and reward from everyday experiences. This is supported by biological evidence for an overactive amygdala and for deficits in the brain’s reward circuitry. Cognitive behavioural therapy (CBT) aims to correct the emotional biases of depressed patients by restructuring the way they think about and react to stressful, negative mood-inducing situations. For example, a depressed person may overgeneralise when drawing some negative conclusion about a specific event. In this case, it is important to make them realise that outside of that specific event, they are responsible for many positive outcomes as well, i.e. they are not a failure and are capable of good things. Another aspect of CBT may be aimed at overcoming defeatism – for example, someone may believe that they’ll never be capable of completing a particular task, and get down on themselves because of that. In this case CBT would aim to make the patient realise that success often requires failures at the start, but that the key is to make a start and to improve on what was achieved in the first attempt. CBT is about re-framing the way patients think of themselves so that they can leave behind the self-defeating negativity characteristic of major depression.

Pharmacological approaches - SSRIs

The medicines most commonly used for treating depression are so-called SSRIs and SNRIs, which act to increase the amount of serotonin (SSRI), or serotonin and noradrenaline (SNRI), at synapses. Around 50 years ago, the depressed brain was proposed to be deficient in these neurotransmitters, and the application of SSRIs/SNRIs theoretically restores ‘normal’ neurotransmission in the depressed brain. The history and efficacy of SSRIs in the treatment of depression is, however, controversial. Furthermore, the rate of remission for patients prescribed these drugs is only ~30%, and even in successful applications, there is a significant lag in the time it takes for SSRIs/SNRIs to produce an outcome – symptoms typically persist for up to 6–8 weeks even though the primary action of SSRIs/SNRIs occurs in minutes. The reasons for this are unknown and raise questions about how these drugs actually work. One possibility is that they increase neurogenesis (creation of neurons) in the hippocampus, counteracting the cell death that occurs following chronic stress. Consistent with this, a neurogenic effect of SSRIs has been demonstrated in animal models, although debate remains regarding these findings. Even though the hippocampus is not directly implicated in much of the neurobiology of depression, it has extensive connectivity with important regions such as the amygdala, prefrontal cortex, and NAc, and restoring hippocampal function may help these circuits operate more normally.

Electroconvulsive Therapy

The time lag associated with SSRIs is both a conundrum and, therapeutically, a concern. Chronically depressed patients are often suicidal, and a delay of several weeks for antidepressants to work (if they work) could so easily be deadly. A more effective approach to depression-related suicide prevention is electroconvulsive therapy. ECT involves delivery of electric current through the scalp to intentionally trigger a seizure within the brain. Although treatment is visually confronting and appears almost medieval in nature, ECT achieves remission rates of ~50% in patients who were unresponsive to SSRIs/SNRIs, although relapse had sometimes occurred by 1 year after treatment. ECT remains the gold standard for treating major depression, even though its mechanisms are largely unknown. One possibility is that it acts to increase neurogenesis in the hippocampus (similar to SSRIs/SNRIs). Although ECT is typically the most effective current treatment, it also has a notable side effect in that it commonly causes temporary memory loss in patients, lasting a few weeks to months. Moreover, as with other current treatments, a large portion of patients remain unresponsive to electroconvulsive therapy. This alone drives the desire for more effective therapeutic approaches to depression.

New treatments

Currently available treatments for depression produce lasting remission in only 30–50% of patients. This means a lot of people slip through the cracks, and suicide rates are very high (~20–30%) amongst these people. Developing improved therapeutics is obviously desirable, and if possible, the treatment should have rapid effects to limit people acting on their suicidal thoughts. Two relatively new treatments – ketamine (a drug) and deep brain stimulation – are showing some promise in relieving depression symptoms in humans.

Pharmacological - Ketamine

Ketamine may be best known for its use as a recreational drug, but it’s also commonly used legally as an anaesthetic. Whereas SSRIs and SNRIs affect the neurotransmitters serotonin and noradrenaline, ketamine acts on a receptor for the transmitter glutamate, blocking the receptor yet paradoxically increasing neurotransmission. Ketamine has rapid antidepressant effects (onset <2 hours) that last weeks, meaning that is effective in the short-term for reducing the risk of suicide. However, because of its potential for abuse and addiction, it is unlikely that ketamine itself will be clinically useful. Instead, it will probably serve as a reference around which new compounds – which lack the unwanted side effects of ketamine itself – can be developed. So far, researchers have developed closely related drugs that minimise side effects, but these have proven less effective in actually relieving depression. Because of current concerns with addiction and abuse, it will also be useful to decrease the frequency with which ketamine (or derivatives) must be given; in other words, to increase the duration of ketamine’s antidepressant effect beyond a few weeks.

Deep Brain Stimulation

Deep brain stimulation (DBS) delivers constant, high-frequency electrical stimulation to a small target region of the brain through an implanted electrode. DBS is best known for its use in relieving the motor symptoms of Parkinson’s disease, but has also been used to treat aspects of Tourette syndrome, dystonia and essential tremor. More recently, DBS has been trialled for non-motor related disorders such as obsessive-compulsive disorder, addiction, and depression. The concept in all of these is the same – stimulate a particular brain region at high frequency to reduce the symptoms (although the reason DBS works for any disorder is not clear). What differs is the location of the stimulation electrode and the actual stimulation parameters used (e.g. frequency, pulse duration, pulse amplitude).

Schematic of deep brain stimulation apparatus. The brain location at which the probes are placed depends on the condition being treated.

DBS is really a last resort for treating depression. This is because the procedure is invasive, requiring surgery to open the skull, implantation of the electrode in the target region, and placement of a pulse generator and battery within the chest. For this reason, non-invasive stimulation approaches are also being trialled for depression relief (e.g. transcranial magnetic stimulation, or TMS). So far, the data on the effectiveness of DBS for treating depression are pretty scarce. Most studies have been of the so-called “open-label” variety, meaning that doctors and patients know that the treatment is being applied. This leaves wide open the possibility that any observed effects are due to a placebo effect. Nevertheless, in such open-label studies, DBS of the NAc and some other target brain regions have proven effective. Importantly given the potential for a placebo effect, some studies have observed changes in depressive symptoms upon removal of the stimulation, even if the patient was unaware (blind) that DBS was no longer active. Furthermore, subsequent reinstatement of DBS was associated with improvements in symptoms. Importantly, no adverse side effects have been reported following DBS treatment for depression. These findings indicate that DBS may hold some promise for treating depression that is resistant to other forms of therapy, such as psychotherapy, pharmacotherapy, or ECT. However, more robust evidence is needed in the form of better controlled clinical trials.

Summary

Depression remains one of the most socially and economically devastating mental health disorders worldwide. Behavioural observations indicate the importance of stress in initiating chronic depression, and of the regulation of positive and negative thoughts in the depressive symptomology. These thoughts are supported by neurobiological evidence indicating that the prefrontal cortex regulates how well we cope with stress, and affects the activity of the nucleus accumbens (NAc) and amygdala to balance reward motivation and the impact of negative emotions, respectively. Current treatments, including psychotherapy, pharmacotherapy and electroconvulsive shock therapy, can be effective, but a relatively large proportion (~50%) of patients remain resistant to treatments. Future therapies will include novel pharmacological targets, such as ketamine derivatives, and focussed electrical stimulation of brain regions implicated in depression, such as through DBS.