New Treatments for Depression: DBS and Ketamine

Pulitzer Prize Winning Author William Styron

Numerous studies have investigated deep brain stimulation (DBS) as a therapy for TRD (Treatment Resistant Depression). We performed a meta-analysis to determine efficacy and a meta-regression to compare stimulation targets. We identified and screened 1397 studies. We included 125 citations in the qualitative review and considered 26 for quantitative analysis. Only blinded studies that compared active DBS to sham stimulation (k = 12) were included in the meta-analysis. The random-effects model supported the efficacy of DBS for TRD (standardized mean difference = −0.75, <0 favors active stimulation; p = 0.0001)… While enthusiasm for DBS treatment of TRD has been tempered by recent randomized trials, this meta-analysis reveals a significant effect of DBS for the treatment of TRD. Additionally, the majority of trials have demonstrated the safety and efficacy of DBS for this indication. Further trials are required to determine the optimal stimulation parameters and patient populations for which DBS would be effective. 

DBS for Treatment Resistant Depression

Deep brain stimulation is still being explored and is far from perfect. But already the technique is leading to new knowledge about the workings of human brains and is uncovering possible new approaches to useful, life-saving intervention.

Deep Brain Stimulation for Depression YouTube

The image above comes from a YouTube video describing the results of ongoing deep brain stimulation experiments for the treatment of resistant depression. The brain utilizes a large number of discrete networks to accomplish its many tasks throughout the day. It is postulated that the brain sometimes falls into a “dysrhythmia,” similar to the dysrhythmias of the heart. As neuroscientists and clinicians learn more about these networks and their normal rhythms, they will be better able to intervene in the functioning of the brain, where necessary.

Perhaps a million people die from suicide around the world, every year. That is stark evidence that current approaches to the treatment of depression are not adequate to the need. Modern antidepressant drugs are safer than the older versions, but not quite half of persons who take them fail to achieve lasting benefit from them.

The latest studies suggest that deep brain stimulation may provide around 50% remission rates among drug resistant depressives, which makes that treatment worth considering for those whose lives might otherwise be full of misery — or may even be lost to suicide in time. It is also important to understand that depression is itself an independent risk factor for many common causes of physical morbidity and mortality including heart disease.

Ketamine for Treatment Resistant Depression

Although major depressive disorder (MDD) is amenable to pharmacotherapy, up to one-third of patients fail to respond to treatment [2] and may remain at risk of suicide [3]. Suicidal ideation (SI) is a common symptom in patients with MDD and its development represents a critical step in the progression from suicidal thoughts to attempts [4]. SI often requires rapid intervention(s) but very few treatments are effective in reducing SI and none are fast-acting [5].

Subanaesthetic doses of intravenous (IV) ketamine, an ionotropic glutamatergic N-methyl-d-aspartate (NMDA) receptor antagonist, have been shown to elicit rapid, albeit transient reduction in depressive symptoms in patients with mood disorders [6]. A recent meta-analysis has also provided evidence of the efficacy of ketamine to acutely decrease SI [7]. It has been postulated that these two therapeutic actions are mediated by an increased transmission at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [8]. While preliminary evidence of the effects of ketamine on SI primarily came from secondary analyses of randomized controlled trials investigating the antidepressant effects of single ketamine infusions [9,10,11,12], several recent trials have examined change in SI with ketamine as a primary outcome measure [13,14,15].

Reducing Suicidal Ideation with Ketamine

Two things are intriguing about the use of ketamine as an antidepressant: It is very quick — which can be crucial for effective suicide prevention — and it works in many people who are resistant to ordinary antidepressant drugs.

Just as in DBS, the use of ketamine for TRD is still in the early discovery stages. But the results are promising. Given the extent of the global problem of TRD and suicidal ideation — and suicide — the promise of a rapid acting, effective, and safe treatment for suicidal ideation is welcome.

Other treatments for treatment resistant depression include ECT, vagal nerve stimulation, transcranial magnetic stimulation, magnetic seizure therapy, cognitive behavioral therapy, and mindfulness therapy. More

The team presenting the video above has developed an individualized targeting method to optimize placement of electrode for precise “current steering.” This type of precise targeting which is customized to each individual’s brain, appears to be a useful element of the overall treatment strategy. If you choose to watch the above video to the end, the “spin down” of the girl’s mood as her brain implant is turned off, is heart-breaking.

For those who are receptive, my recommendation for TRD would be mindfulness meditation with an insightful and compassionate teacher, or cognitive behavioral therapy from an experienced and wise therapist. But rapidly acting drugs such as ketamine, and experimental approaches such as magnetic seizure therapy and TMS, may provide quick and safe remission from suicidal ideation without the need for surgically implanted electrodes — which is required for the use of DBS and Vagal Nerve Stimulation.

And, as always, the use of laughter and smiles is always recommended — except where it might be taken the wrong way by persons you would not wish to offend. If your psychic energy levels allow, the watching of your favorite comedy films can provide amazing short term relief from despondency.

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