Tag Archives: psychiatry

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

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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.

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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).

Psychosis Research. Where have we been & where are we going?

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phenotype and genotype

The Institute of Psychiatry at The Maudsley is the largest centre for psychiatric research in Europe. Recently a group of leading researchers were tasked with summarising an area of research as it pertains to psychosis and psychopharmacology.

The outcome was a series of short lectures, delivered to a lively audience of psychiatrists, mental health workers and psychologists at The Maudsley. The lecture slides and audio are now available below and constitute a unique training resource for those who treat patients.

1. Sir Robin Murray,
“Psychosis research: Deconstructing the dogma“
2. David Taylor,
“Current Psychopharmacology: Facts & Fiction“
3. Oliver Howes,
“How can we Treat psychosis better?“
4. Marta DiForti,
“An idiot's guide to psychiatric genetics“
5. Sameer Jauhar,
“Ten psychosis papers to read before you die!”
6. Paul Morrison,
“Future antipsychotics“

 

Neurophysiology can free psychiatry from it’s dependence on metaphor.

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el Greco

For psychiatry to progress, it can take as it's starting point the most up to date thinking on how the nervous system operates. This necessitates an appreciation of how neurons communicate with each other, how circuits emerge and how CNS tissue is sculpted in the very act of processing information. A short synopsis of some of the main themes in contemporary neurophysiology is presented here. First we shall consider the two main theories of how information is processed in the here-and-now. Then we shall look briefly at spike-timing dependent plasticity, the latest and arguably the most elegant form of plasticity within the brain, which synthesises many strands.

Information Processing

Special gnostic cells

There are two major theoretical accounts of how neural tissue “performs its computations”. The first account postulates the existence of ‘special cells’ at the top of a processing hierarchy. These cells are less ‘concerned’ by the raw ‘building blocks’ of sensory experience – orientation, brightness, colour, pitch etc. Instead, they respond (‘fire’) to whole objects (Gestalts), regardless of perspective, illumination and all the other idiosyncrasies that make up a perceptual scene. The metaphor of the ‘grandmother cell’ captures the idea. “Each time my grandmother comes into consciousness, via any of the sensory channels or in imagination, a ‘special’ cell, somewhere in the brain, is “active”.

The main criticism of the ‘grandmother cell’ hypothesis [aside from its prioritising of perception over thought & movement] is that there are far more potential percepts, than available neurons. Another criticism is that by focusing exclusively on feed-forward pathways, the hypothesis ignores the anatomical 'reality’ of extensive feedback pathways. Nevertheless, in-vivo electrophysiological work in humans undergoing neurosurgical procedures has provided evidence that there are neurons in the medial temporal lobe, which have the characteristics of grandmother cells.

Dynamic Assemblies

The second account prioritizes flexible, dynamic assemblies of neurons over ‘special’ cells. An assembly is defined as a constellation of neurons, which are firing action-potentials within the same narrow time-window (synchronously). Here, processing is a more ‘democratic affair’, and no special cells are required. Feedback and feed-forward connections are equally important, as the network (the assembly) reaches a consensus. Assemblies are transient entities, emerging for a period before ‘dissolving’, perhaps to ‘reappear’ at a later instant. A temporarily ‘dominant assembly' may ‘recruit’ other ‘partners’. Allegiances are flexible, with co-operation at one instant and competition at another. And over longer periods of time, assemblies can become – stronger; by virtue of sheer repetition and the ‘rules’ of long-term-potentiation (LTP), particularly if monoamine systems are co-active – or weaker; if the ‘content’ is fleeting or insignificant. Network oscillations (rhythms) provide a metronome, to ensure that the right cells fire in synchrony. Gamma (30–200 Hz) rhythms ‘bind’ local assemblies, whereas lower frequencies (theta, alpha, and beta) sub-serve long-distance communication between brain areas.

Of course, it is entirely feasible that the CNS makes use of both schemes described above [special cells & dynamic assemblies]. Processing power may reach grand heights when special [gnostic] cells come together as an assembly.

Sculpting CNS tissue

Spike-timing-dependent plasticity (STDP) depends on the conjunction of pre and post-synaptic events, within a narrow time envelope, of the order of tens of milliseconds or so. In the most straightforward version, a synapse is strengthened if a pre-synaptic input occurs immediately prior to a post-synaptic action potential (AP). If on the other hand, the input arrives in the immediate aftermath of a post-synaptic AP, the synapse is weakened. Pre and post-synaptic events beyond the critical time-window (i.e. unpaired ‘events’) leave synaptic strength unchanged. This shows how the precise timing of neuronal firing impacts upon the network. [And this impact is structural, as well as biochemical, Link]. Two aspects of STDP are notable:

1. Conventional neuromodulators appear to ‘tweak’ STDP. Actually ‘tweak’ is an understatement. The presence of a modulator such as dopamine can transform a normal pre-> post strengthening into a depression instead. More succinctly, dopamine can determine the direction of plasticity (+ or -).

2. The critical time window of STDP (tens of milliseconds) is in exactly the same ‘ballpark’ as network oscillations in the gamma band (period ~25ms).

The elegance of STDP is that it begins to reveal how apparently unconnected phenomena [brain-oscillations and neuromodulator systems], are integrated within a fundamental CNS function – how synapses and circuits are sculpted over time.

 

Psychosis & Schizophrenia: What’s in a name?

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Psychosis?

this way that way

In general, psychosis refers to the presence of hallucinations (false perceptions), delusions (false, fixed ideas, which carry overwhelming significance for the patient), loss of insight, ipseity disturbance and thought disorder. For over 100 years the psychoses have been divided into organic and functional categories.

Organic denotes an identifiable systemic or central pathology. Organic psychoses can be secondary to endocrine disorders (thyroid disease); metabolic disease (acute intermittent porphyria); autoimmune disorders (paraneoplastic limbic encephalitis, NMDA receptor encephalitis [Link]); infection (herpes simplex encephalitis); seizures (temporal lobe epilepsy); space-occupying lesions; stroke; head-injury; demyelinating diseases (metachromatic leukodystrophy); neurodegenerative disease (Lewy-body dementia); basal ganglia disorders (Wilson’s disease); nutritional deficiencies (B12 deficiency); medications (acyclovir); environmental toxins (thallium); and psychoactive drugs (LSD, ketamine, cannabis and stimulants [Link]).

The identification of an organic psychosis depends upon a thorough history, physical examination and the prudent use of laboratory investigations. Identification of an organic cause of the psychosis can dramatically change the subsequent management and prognosis.

Functional psychoses are diagnoses of exclusion (i.e. exclusion of identifiable organic pathology). There are as yet no diagnostic tests. Diagnosis is made of clinical grounds (symptoms/signs) according to the criteria in the Diagnostic & Statistical Manual of the American Psychiatric Association (APA, DSM-IV-TR) or the International Classification of Diseases of the World Health Organisation (WHO, ICD-10) [Link]. The two classification systems are broadly similar. They subdivide the functional psychoses into schizophrenia (paranoid type, disorganised/hebephrenic type, catatonic, undifferentiated, residual [and simple in ICD-10]); persistent delusional disorders, schizophreniform disorder (DSM-IV-TR), brief psychotic disorders and schizoaffective disorder. Psychotic symptoms can also occur in bipolar disorder and major depressive disorder.

Schizophrenia?

For a DSM-IV-TR diagnosis of schizophrenia, the following criteria must be met: 1.The presence of characteristic symptoms [at least two, (or one if delusions are bizarre/or if auditory hallucinations form a running commentary or discuss the patient.)] for most of the time for one month (or less if treated), which can be delusions, hallucinations, disorganised speech, grossly disorganised behaviour or negative symptoms (blunted affect, alogia or avolition). 2. Social or occupational dysfunction. 3. Continuous signs of disturbance for six months (including one month of psychotic symptoms). Caveats are that the symptoms cannot be secondary to a mood disorder, a pervasive developmental disorder, or as a result of an identifiable organic illness – (the last of which would takes us back to the top of the page here).