Modern Management of Treatment-Refractory Depression and OCD

Thursday, 12 April 2018

From 1900 to 2100

Medico-Chirurgical Hall

Dr David Christmas is a Consultant Psychiatrist in the Advanced Interventions Service, a Scottish National Specialist Service for the assessment and treatment of chronic, treatment-refractory depression and Obsessive-Compulsive Disorder (OCD). He has been in his current post since 2006. Prior to this, he was a clinical lecturer in the University of Dundee.

His research interests include neuroimaging of mood disorders and the neurosurgical treatment of chronic, treatment-refractory depression and OCD. He is a proponent of evidence-based psychiatry.


The President welcomed the company to the meeting. He introduced Dr David Christmas, Consultant Psychiatrist in the Advanced Interventions Service and based in Dundee, inviting him to give his talk on ‘Modern Management of Treatment-Refractory Depression and OCD’.

Dr Christmas explained that he had been a Consultant in Tayside since 2006 working in a Nationally funded, supra-specialist Advanced Interventions Service (AIS). With the main focus of the unit’s work being on treatment-refractory depression and OCD, he began with a few statistics relating to each condition.

Major depression affects 13% of people in their lifetime and almost 4% of the population within any 12 month period. It is twice as prevalent in women, most commonly starts in the 3rd decade, lasts more than 2 years in up to 20% of sufferers, and has a 35% recurrence rate.

OCD affects 2-3% of people and a little over 1% of the population within a 12 month period. It has equal gender prevalence, starts earlier in males (6-15 yr) than females (20-29 yr) with often long delays before diagnosis and treatment. Its detection is obscured by reluctance of sufferers to divulge symptoms, by its being overlooked as a major component in some diagnosed with anxiety disorders, and when its rituals are so bizarre as to engender a label of psychosis.

Application of the term ‘treatment-refractory’ to depression is held by the AIS when the condition is unresolved after 4 or more trials of drugs from different classes , 2 or more trials of psychotherapy or of pharmacological augmentation therapy, and at least 8 ECT administrations. If considering referral for neurosurgical treatment for depression, the thresholds are much higher still.

These guidelines are never absolute and perhaps even more complex in relation to OCD: previous failed trials of 3 selective serotonin uptake inhibitors (SSRIs) including clomipramine, 2 augmentation trials (including risperidone) and 1 ‘intensive therapy’ trial.

Moving to newer potential therapies for depression, Dr Christmas explained there was little to commend new pharmacological agents over their predecessors either in terms of efficacy or adverse effect profile. Vertioxetine was possibly marginally more effective – but certainly far from universally useful. Ketamine, which produces a state of dissociation has been the subject of 5 recent systematic reviews which show that it has a short-lived beneficial effect for a few days but to date has not been shown to have useful longer term efficacy and, indeed, in some studies indices have been less favourable by the end of a week of ketamine treatment. It seems unlikely that this class of agent will have any lasting impact until a preparation with a much longer effect on mood can be developed.

Dr Christmas then moved on to describe several newer brain stimulation therapies for depression, concluding that none is close to coming into routine clinical usage at present.

 Transcranial Magnetic Stimulation (TMS) typically comprises around 5 episodes of 20-30 minutes duration per week for 2 to 4 weeks with an external pulsed magnetic field targeting the dorsal prefrontal cortex.  It requires no anaesthetic, is apparently safe and so is currently deemed suitable for use although 20 systematic reviews suggest a modest effect, similar in magnitude to drug therapy, and variable efficacy across individual patients. Evidence shows that TMS is clearly inferior to Electro-Convulsive Therapy ECT). It may however be useful in e.g. perinatal depression, those intolerant of high dose antidepressants, those having marked cognitive adverse effects of ECT and those unable to have repeated general anaesthesia.

Transcranial direct current stimulation (tDCS) is another approach that has been the subject of short-term studies with low numbers of patients and hence not robustly evaluated. Although there is little evidence of benefit, tDCS equipment is available for general sale on the internet with claims that it improves performance in computer gaming.

Transcutaneous Vagus Nerve Stimulation (tVNS) has been recommended by some for some time for refractory epilepsy and more recently tried for refractory depression. A generator is surgically implanted with an output lead surrounding the vagus nerve. The generator can be transcutaneously reprogrammed. A simpler approach, recognising that the vagus innervates part of the external auditory canal could potentially allow tVNS to be used less invasively. While this treatment may have some potential there is currently no compelling evidence of efficacy.

Deep Brain Stimulation (DBS) is another invasive therapy that has numerous putative target areas in the brain; the close proximity of several of these and lack of certainty about the distribution of potential effects around an electrode make accurate assessment of effects on different target areas difficult to assess or interpret. A registry of over 300 trial cases exists with the suggestion that around 40% of those with refractory depression will respond. Two randomised  controlled trials of real and sham DBS comprising 30 patients treated for 4 months, and 230 patients treated for 6 months, respectively, have shown almost identical improvement in up to 50% of both placebo and treatment groups! This intriguing finding suggests that DBS is not, per se, effective but clearly some further understanding is needed for why both treated and sham groups have substantial response rates.

Turning to the management of OCD, it was stated that serotonin reuptake inhibitors including Clomipramine as well as selective agents (SSRIs) are the mainstay of treatment. Regularly, higher doses of these agents are needed than are used for depression (e.g. 60 mg fluoxetine cf 20; 200 mg sertraline cf 50-100; 250 mg clomipramine cf 50-100). DBS, as in the depression trials, is said to be effective in 40-50% of cases with investigators in different nations apparently favouring a different favourite target site within the brain. There is little in the way of RCT data to give any assurance that sham DBS would have any lesser effect than ‘active’ treatment.

Dr Christmas then moved on to say more about the work of the AIS in Ninewells Hospital which was established with central Scottish Government funding in 2006. Much strategic emphasis has been put on differentiating between the intended quaternary level status of this unit, with the requirement to fill tertiary level need, there being no tertiary level psychiatry services anywhere in Scotland. This means that the majority of the work involves assessing referrals direct from secondary care. It was noted that referral requires no extra expenditure from referring health board to this specialist unit with its top-sliced central funding.

All of the referrals, numbering up to 40 per year, are subject to a highly detailed, critical review of the case notes and structured multidisciplinary assessment, resulting in clear treatment recommendations going back to the referring clinician. Although there are links with neurosurgical services in the National Hospital for Neurology and Neurosurgery in Queens Square, London very few patients (0-4 per year), are referred on from AIS for consideration of this most radical treatment option.

Over the years the AIS staff has gained expertise in accurate diagnosis of referrals with apparent treatment-refractory OCD. Up to 30% of patients referred have the main diagnosis revised following AIS assessment with some relabelled as having autistic spectrum disorders, alternative anxiety syndromes or even underlying psychosis-driven compulsive behaviours. Untangling a precise diagnosis in some instances remains complex and perhaps even elusive.

It is similarly difficult to be precise about appropriate referral criteria that allow the AIS to be helpful without taking over the secondary care role for referred patients. There have also been ongoing challenges of accurately defining what AIS can provide where staff and time resources are generally diminishing. Intensive inpatient treatment is occasionally thought appropriate, usually in the form of Exposure and Response Prevention (ERP) therapy for OCD. Perhaps 4-6 admissions per year for ERP will each receive daily therapy over 3-4 weeks totalling up to 60 hours of personal treatment. Response is limited and similar to other complex OCD treatments in producing a reduction from around 30 to 20 in the Yale-Brown Obsessive Compulsive Scale. Despite this limited outcome, it is noted that there are no alternative interventions that are regularly more efficacious.

Dr Christmas summed up by saying that for depression there is little new; ketamine is interesting but currently too short-lived to be useful. Possibly the use of psychedelic agents will be a future area for research. Most developmental work is in neuro-stimulation but there are few really useful outcomes of this to date. For OCD, the best advice is to use existing drugs better and, where tolerated, in higher doses. DBS may be better for OCD than depression but this is not yet substantiated.

The presentation generated many questions and comments from the audience. The discussion included a request for advice on how existing therapies could be more effectively used in primary (and secondary) care with a major emphasis being on adequate duration of drug treatment e.g. over a year for a first episode of depression and perhaps up to 5 years to prevent relapse. The possibility of genetic testing increasing the potential for targeting therapies more specifically was thought unlikely as no clinically useful associations had been demonstrated to date. Further discussion of the equivalence of active and sham treatment in DBS trials led to considerations that it may not always be apparent what the effective component in a therapy may be giving rise, for example, to the idea that in the disorders under consideration, it may be more important to have the correct therapist than the correct therapy for the case in question. It was recognised that the recommendations made by the AIS may not be implemented as they are impractical for local, secondary care services to provide and it was therefore put to the speaker that perhaps his unit could do more to address the need for better resourcing of services – staff and skills - around the country. The established place for maintenance ECT in treating chronic depression was acknowledged. The suicide risk for patients referred to AIS was said to be low leading to a final suggestion that instilling hope in the relevant patient group, such as could result from referral to AIS, may be one of the most important ‘interventions’ of all.

The President delivered a vote of thanks and presented Dr Christmas with a copy of ‘The Heritage of the Med Chi‘.

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