Treatment Resistant Depression: future prospects

Many patients go through years and years of depression which stubbornly resists treatment. Therapy, SSRIs, even ECT, can all fail to provide any shift.

But a recent paper by Oxford psychiatrist Phil Cowen brings some light. In a readable and straightforward account, Cowen weighs-up the various options that are available, when first and second line antidepressant treatments are ineffective.

Depressed patients, GPs and psychiatrists will find the text very useful in selecting options – and in keeping hope alive. Topics covered include various combination and augmentation strategies and their statistical likelihood of success. Also, an expert appraisal of several new approaches, which are showing promise – including ketamine and psilocybin. Recent findings with pramipexole, a drug already used in neurology, are especially encouraging.

The full text published in the journal Psychological Medicine is available here.


Zapping the Blues: The effectiveness of magnetic and electrical stimulation for treatment-resistant depression.

Blake glad day

Treatment-resistant depression (TRD) affects 1-3% of the population. Recently Holtzheimer & Mayberg reviewed the effectiveness of a range of new and promising techniques based on direct neural stimulation. The list includes Transcranial magnetic stimulation, Transcranial direct current stimulation, Magnetic seizure therapy, Vagus nerve stimulation and Deep brain stimulation.

The prototype of course is ECT (electroconvulsive therapy), which is a highly effective treatment for melancholic depression, but suffers from the effects of a negative historical portrayal. The authors present a balanced and elegant appraisal of the current state of affairs for the new techniques which can be read here in full. The summary points are as follows…

Transcranial magnetic stimulation (TCMS)

– FDA (US food & drug administration) approved.

– Uses rapidly alternating magnetic fields to induce current in the underlying cortex.

– 10 to 30 treatment sessions over 2-6 weeks.

– Controlled trials have been positive.

– Response rates in TRD: 20-40%.

– Remission rates in TRD: 10-20%.

– Repeated courses may maintain initial benefits.

Transcranial direct current stimulation

– Delivers a low-intensity direct current to the underlying cortex.

– 5 times per week treatments for several weeks.

– Fewer side effects than TCMS?

– Antidepressant effects claimed from a small number of open and controlled studies.

– Response, remission & relapse rates are unclear.

Magnetic seizure therapy

– Seizures are induced using a transcranial magnetic stimulation device.

– Antidepressant effects from a small number of open studies.

– Claims for less side-effects than ECT, but may be less effective.

Vagus nerve stimulation

– FDA (US food & drug administration) approved.

– Electrical stimulation to the left vagus nerve through an implanted pulse generator.

– Open-label response rates in TRD: 30-40%.

– Open-label remission rates in TRD: 15-17%.

– No evidence for efficacy in a large controlled study.

– Simple surgical procedure.

Deep brain stimulation.

– Precise neurosurgical implantation of electrodes using stereotactic techniques.

– Remission rates in TRD: 40-60%.

– Relapse in remitted patients is uncommon.

– Complex surgical procedure.

Holtzheimer & Mayberg conclude, “Neuromodulation for depression is at an exciting and promising stage of development, and continued well-conducted research will help clarify and realize its potential“.


Ketamine for resistant depression: Outstanding promise, outstanding issues.

Outstanding Promise.

Ketamine has been around for many years, firstly as a dissociative anaesthetic and then as a psychedelic drug. But it might become best known for it's powerful antidepressant properties (Berman et al 2000; Zarate et al 2006). Compared to existing antidepressants, which take around 2 weeks to work, ketamine exerts a large antidepressant effect on the first day of treatment.

depression ketamine murrough

Figure 1: The antidepressant effect of ketamine over 6 treatment sessions. The improvement on day 1 (measured using the MADRAS scale) was predictive of the response achieved following the sixth treatment session.

The robust antidepressant effect of ketamine also occurs in patients who have not found relief with existing drugs or with ECT. In the latest study to be reported, 24 patients with treatment-resistant depression underwent up to 6 sessions of intravenous ketamine (0.5mg/Kg in 40 mins) over ~2 weeks. Over 70% of patients responded to ketamine, and the overall reduction in depression was large and rapid (Murrough et al 2013) (Figure 1).

Outstanding Issues.

To date a major issue has been the lack of persistence of the antidepressant effect. In previous studies, involving a single ketamine treatment, depression returned within one week of the session or less. In the study by Murrough et al, this was extended to an average of 18 days. This is an improvement, but further work will be needed to solve the problem of the relatively short-lived antidepressant effect of ketamine.

An understanding of the mechanism by which ketamine alleviates depression may be necessary if we are to extend the duration of it's beneficial effects. Pre-clinical work suggests that ketamine boosts the health and integrity of synapses and neuronal networks. Much of the action is believed to take place within dendritic spines, and involves local protein synthesis (Duman et al 2012) (Figure2).

ketamine mechanism

Figure 2: The antidepressant effects of ketamine may depend upon activation of mTOR and local protein synthesis in dendritic spines.

Two molecules of relevance are mTOR and GSK-3. Ketamine enhances local protein synthesis by activating mTOR and by inhibiting GSK-3. [GSK-3 inhibits mTOR]. A drug, such as lithium, which inhibits GSK-3 might enhance the antidepressant effect of ketamine. This has now been demonstrated in pre-clinical studies (Liu et al 2013). The clinical question, which will now be addressed in trials is whether lithium treatment extends and enhances the antidepressant effects of ketamine. Lithium has been used for treatment-resistant depression for many years, and has a good evidence base (Bauer et al 2010) so that the combination of ketamine and lithium presents as an interesting and relatively straightforward strategy for stubborn depression.

However it is somewhat odd that the proposed mechanism for ketamine involves new protein synthesis and synaptogenesis (which take time, and are sustained) whereas the clinical effects of ketamine are very rapid (and transient). Other mechanisms may have more explanatory power. For instance a recent fMRI study showed that ketamine decreased the connectivity of limbic and prefrontal regions which are known to be overactive in depression (Scheidegger et al 2012). More provocatively, it appears that the antidepressant effect of ketamine depends upon the extent of the acute psychological reaction produced by the drug. Although the dissociative/psychedelic properties of ketamine are sometimes regarded as unwanted “side-effects”, a recent paper showed that the acute psychedelic and subsequent antidepressant effects are related (Sos et al 2013).

Guidelines for the Management of Bipolar Disorder.


The first German-language guidelines for the management of bipolar disorder were published in 2012, and now, an abbreviated English translation is available online for free [link].

The German Society for Bipolar Disorder (DGBS) and the German Association for Psychiatry & Psychotherapy (DGPPN) set up a project group, a steering group and 6 working groups made up of psychiatrists, psychotherapists, patients and their families. Devoid of any industry funding, their intention was to providedecision-making support for patients, their families, and therapists“. Following an extensive literature review, and ten consensus conferences they concluded:

“Bipolar disorder should be diagnosed as early as possible. The most extensive evidence is available for pharmacological monotherapy; there is little evidence for combination therapy, which is nonetheless commonly given. The appropriate treatment may include long-term maintenance treatment, if indicated. The treatment of mania should begin with one of the recommended mood stabilizers or antipsychotic drugs; the number needed to treat (NNT) is 3 to 13 for three weeks of treatment with lithium or atypical antipsychotic drugs. The treatment of bipolar depression should begin with quetiapine (NNT = 5 to 7 for eight weeks of treatment), unless the patient is already under mood-stabilizing treatment that can be optimized. Further options in the treatment of bipolar depression are the recommended mood stabilizers, atypical antipsychotic drugs, and antidepressants. For maintenance treatment, lithium should be used preferentially (NNT = 14 for 12 months of treatment and 3 for 24 months of treatment), although other mood stabilizers or atypical antipsychotic drugs can be given as well. Psychotherapy (in addition to any pharmacological treatment) is recommended with the main goals of long-term stabilization, prevention of new episodes, and management of suicidality. In view of the current mental health care situation in Germany and the findings of studies from other countries, it is clear that there is a need for prompt access to need-based, complex and multimodal care structures. Patients and their families need to be adequately informed and should participate in psychiatric decision-making“.

The abridged guidelines (in English) are available here.


Natural antidepressants & new brain cells

New Brain Cells

In the last decade it has become clear that new cells can form in the adult brain. This happens in a region known as the hippocampal complex. The hippocampal complex is found deep inside either temple and is crucial for memory and emotion. The hippocampal complex inhibits the human stress response, but can itself be damaged by persistent stress, leading to a vicious cycle in which the stress response is amplified further and depression ensues.

hippocampus from nieuwenhuys et al

The hippocampal complex is found in the temporal lobe, and has a crucial role in regulating the stress response.

Experimental work suggests that neurogenesis (the birth of new neurons) in the hippocampal complex is vital for the action of conventional antidepressant drugs. Exercise and enriched environments also promote neurogenesis, whilst stress has the opposite effect.The current picture is that hippocampal health (including the birth of new neurons) is essential for protecting the organism against the effects of stress, so that if hippocampal functioning is compromised, anxiety and depression can emerge.


Natural Antidepressants

There has been recent interest in the antidepressant properties of a natural molecule called curcumin. This substance is found in the herb turmeric. As well as a foodstuff, turmeric has been used for centuries in traditional Indian medicine (Ayurveda). In pre-clinical studies, curcumin exhibited clear antidepressant effects.


Research has focused on the mechanism of action of curcumin. Remarkably it appears that curcumin can also increase the birth of new neurons in the hippocampal complex. This is an intriguing finding which hints at the possibility of a new class of antidepressant drug.

A new paper from researchers at King's College London provides an excellent summary of work in this area. The full paper can be read here.