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Future treatments for depression

The World Health Organization (WHO) estimates that by 2020, depression will be the second greatest contributor to the global burden of disease. Up to 30 per cent of depressive episodes do not improve with medications or psychotherapy, so there is an overwhelming need for new and better treatments.

While many effective treatments in medicine have been discovered serendipitously, modern treatments are often logically developed based on underlying pathophysiology.

A major obstacle in developing treatments for depression is that the neurobiology is only partly understood. However, recent advances may lead to new therapies for depression and the refinement of established treatments.

Personalised treatment
Medications, electroconvulsive therapy and psychotherapies are undoubtedly effective in depression according to the highest levels of evidence.

However, doctors and depressed patients know that two to three medications and/or psychotherapies may have to be tried before they find the ‘right’ one, which is effective and has acceptable side-effects.

This may be due to individual differences in metabolism and neurobiology. Much research now aims to predict individual patients’ responses to a given therapy, matching the right patient to the right treatment.

Blood-flow patterns
Researchers at the Institute of Psychiatry at King’s College London have identified biological factors predicting responsiveness to treatment. Brain blood-flow patterns correctly predicted 80 per cent of responders to cognitive behavioural therapy. The same team has correctly predicted nearly 90 per cent of treatment responders and non-responders using MRI analysis of brain structure. These results await broader validation and replication by independent groups.

Although such tests are unlikely to be cheap and easily available in the near future, they provide a sound neurobiological basis for predicting treatment response and a firm rebuttal of claims that there are no brain changes associated with depression.

Another potential source of hope is the recent publication of several genome-wide association studies (GWAS). These studies scan the genome of thousands of participants for tiny changes that predict medication response.

Gene targets identified using this technology include those involved in neural plasticity and synaptic transmission. So far, each gene change identified is a poor predictor of individual drug response on its own. However, it may be that combinations of genes and their interaction with certain environmental risks will provide better predictive power.

Current research is under way in Trinity College Institute of Neuroscience and the Institute of Molecular Medicine at St James’s Hospital to evaluate specific genetic predictors of response and side-effects during electro-convulsive therapy (ECT) treatment.

Neuroimmune therapies
Depressed patients are more likely to suffer from inflammatory disorders and those with inflammatory disorders more likely to suffer depression.

Treatment with pro-inflammatory cytokines (Interferon-α, for example) can cause a depression-like illness that responds to antidepressant medication, while anti-inflammatory therapies have shown some effectiveness in modulating mood independent of their target effects.

Some of these effects of inflammation are mediated by decreased growth and plasticity of neural networks in the hippocampus, a vital part of the brain in mood and memory.

Bipolar disorder
Some progress has already been made in identifying pro-inflammatory signatures in monocytes of patients with bipolar disorder that may identify those with an inflammatory component to their illness. It is probable that immunotherapy will be used in future treatments for severe and otherwise treatment-resistant depression.

New research suggests that the selective serotonin re-uptake inhibitor (SSRI) medications differ significantly in effectiveness. A recently published meta-analysis provides evidence of greater antidepressant effects of sertraline and escitalopram over others in this class. Such new insight into established medications offers the hope of more effective prescribing.

Many drug companies are developing similar drugs with greater selectivity and better side-effect profiles. These can be expected to be released over the next several years. These and most established drug treatments for depression focus on altering synaptic transmission.

However, many of these medications take several weeks to exert an antidepressant effect, much longer than it takes to change synaptic transmission. Their therapeutic effects may actually rely on changes in gene expression, protein production and neural plasticity occurring over longer time periods.

Future drug targets for depressive illness may include histone deacetylase inhibitors and glycogen synthase kinase inhibitors, which act directly on gene expression.

Histone proteins provide the scaffolding for DNA and also act as on/off switches for certain genes. These molecular switches can be important in the growth of neurons and synapses. They can be switched off by stress, decreasing growth factors and neuronal growth in the brain.

Inhibitors of these molecular ‘off-switches’ have been evaluated for some time as anti-cancer agents. Recently, there has also been preliminary success with these medications in animal models of depression, probably by increasing growth of hippocampal synapses and neurones. Of note, electro-convulsive therapy is the most robust inducer of these positive neuroplastic changes, which may account for its greater therapeutic effects.

The enzyme glycogen synthase kinase 3β (GSK3β) is involved in many of the on/off mechanisms of the cell. It is particularly important in the action of lithium by modulating downstream signalling from the dopamine receptor.

As a result, direct inhibitors of GSK3β are also under evaluation as antidepressant medications. These compounds are at a very exploratory stage of development and it is therefore likely we will wait many years before randomised controlled trials can evaluate their effectiveness in patient populations.

ECT has been the most effective treatment for depression for the last 70 years. A course of six-to-eight treatments of ECT brings remission from depressive symptoms in over 60 per cent of severely depressed patients.

Although many gradual refinements of ECT have occurred since its introduction, both patients and treating psychiatrists have long had concerns about memory side-effects. With this in mind, efforts are under way to further refine the treatment.

In bilateral ECT, electrodes are placed on both sides of the head. High-dose unilateral ECT, with electrodes placed on the right side only, may offer the same antidepressant effect as bilateral ECT but with reduced cognitive side-effects.

A randomised controlled trial of high-dose unilateral ECT versus bilateral ECT is currently under way in St Patrick’s University Hospital (The EFFECT-Dep Trial ISRCTN 23577151). Future refinements may include narrowing the electrical waveform to minimise the cognitive problems associated with this undoubtedly effective treatment.

Other methods
Other methods of brain stimulation have also been under investigation. Vagus nerve stimulation (VNS) has been in use for many years to reduce seizures in treatment-refractory epilepsy.

A pacemaker-like device intermittently stimulates the left cervical vagus nerve. The treatment was observed to have mood-modulating effects and clinical trials for depression were undertaken.

Notwithstanding difficulties in blinding caused by vocal hoarseness and cough, the higher quality controlled clinical trials of VNS for depression have largely failed to show any separation from placebo.Repetitive transcranial magnetic stimulation (rTMS) is the induction of small electrical currents in the brain by an oscillating magnetic field outside the head.

Although the technique showed initial promise as an experimental tool by changing regional brain blood-flow, it has had little or no success versus placebo in controlled clinical trials.

One trial versus ECT demonstrated the vast differences in efficacy between the experimental and established treatments, with 60 per cent of the ECT group remitting versus 16 per cent of the rTMS group.

Transcranial direct current stimulation is a potential treatment currently in development. Small amounts of current are passed through scalp and brain, but the treatment involves no anaesthetic.

There are few side effects except scalp sensations and the treatment has shown limited pre-clinical efficacy in changing regional brain blood-flow. However, small clinical trials have, as yet, failed to support its efficacy in depression.

Deep brain stimulation using fine electrodes placed neurosurgically in the cingulate gyrus has proven effective for treatment-resistant depression in limited case series.

Most patients will continue medications and psychotherapy afterwards, so the treatment is best viewed as an adjunct for people who are severely disabled by depression despite multiple treatments.

Ongoing refinement
Overall, none of these treatments approach the effectiveness and safety of ECT. The ongoing refinement of ECT aims to minimise cognitive side-effects while maintaining the clear effectiveness of this treatment.

In summary, there are many new treatments in development based on growing knowledge about the neurobiology of depression. In the future, we may be better able to match the right patient to the right treatment based on biological and psychological factors.

Emerging insights about the neurobiology of depression may take many years to be translated into sound treatments. However many of the established treatments such as ECT have significant effectiveness that is often overlooked.

(Source: IMT)