New Antidepressants, at last

New Antidepressant class: New mechanism of action

The Mandelbrot Set

Many unfortunate individuals suffer year after year of depression. Depressive illness becomes the defining feature of their lives, as one tablet after another fails, and the psychotherapies reveal themselves as blunt instruments.  For decades, psychopharmacologists have sought a new class of antidepressant, based on new mechanisms, rather those which target the brainstem-derived neuromodulators, serotonin, noradrenaline and dopamine. Finally, there has been a breakthrough. Ketamine, a molecule familiar to the anaesthetists, has repeatedly showed efficacy against stubborn depression. And recently, the s-enantiomer (esketamine) has been fast-tracked for clinical use in the USA after positive results in phase III trials. Ketamine necessitate intravenous administration, whereas esketamine, an intranasal spray, represents a much more practical option for wider clinical use.

The Neurophysiology: Extended consciousness, brain wiring & the personality

Ketamine blocks a receptor for glutamate, the main fast excitatory neurotransmitter in the cortex, thalamus and limbic system. This is the NMDA receptor channel, which is one of the most celebrated components in modern neuroscience, critical for short and long-term plasticity at glutamate excitatory synapses (Collingridge and Bliss, 1995).  Channel opening, and the inward flux of Ca2+, are the prime movers in boosting the strength of individual glutamate synapses, of which there are over 15,000 converging on a single neuron. Over the timeframe of seconds, NMDA receptor activation is essential for supporting conscious mental activity in the vast neural network (Ingram et al., 2018). NMDA receptor activation can also set in train processes which ultimately lead to the long-term structural enhancement of glutamate synapses, the basis for learning and memory. The personality is believed to emerge and develop as the neural network is sculpted and fine-tuned, at the level of individual synapses, by lived experience (Kandel, 1998)(DeFelipe, 2006).

Ketamine impacts upon the neural network, stimulating neurotrophic pathways and enriching neural connectivity, in keeping with the modern idea that depression stems from impoverished connectivity (McEwen et al., 2015).

nmda receptor
The NMDA Receptor.
Glutamate (GLU) and glycine (GLY) activate the NMDA receptor causing channel opening and influx of Na+ and Ca2+. Calcium is a second messenger which activates various from of plasticity. The NMDA receptor is a crucial starting point for working memory and epsiodic memory in the CNS.
Ketamine blocks the pore of the channel, impeding Na+ and Ca2+ influx.

The Psychophysiology: The complete transformation of lived experience & re-birth

Given the physiological importance of glutamate NMDA receptor channels for brain functioning, it is not surprising that ketamine, which blocks the channel pore and impedes the influx of Ca2+, has a profound effect on the psyche. Effects are dose-related. The anaesthetists make use of the fact that ketamine blocks conscious mental content, to the extent that surgical procedures can be carried out in otherwise awake patients, who can support their own respiration. Pain physicians also utilise ketamine, in the knowledge that chronic pain syndromes probably stem from an ingrained plastic adaptation in the cortical areas which support pain perception. For psychiatrists, there is range of ketamine doses which elicit such a complete transformation in lived experience, that some have labelled those experiences as psychotic. In fact, those experiences go much further the usual connotations of psychosis as hallucinations and delusions. Descriptions include, the cessation of time, the dissolution of the ego, near-death experiences and spiritual experiences, perhaps best demonstrated by the use of a plant-derived NMDA receptor channel blocker (ibogaine) as ceremonial entheogen in West Africa.

(There was hope and considerable investment in the idea that a new class of antipsychotic treatments, based on glutamate, could be developed, but this drug-discovery effort failed to materialise in end-stage trials. For depression however, the story has been much more encouraging, and the next phase is now unfolding.)

In West Africa, there is use of a plant-derived NMDA channel blocker called ibogaine. Ibogaine is in the same pharmacological class as ketamine. Ibogaine is used in tribal ceremony to transform conscious experience.

The Upside of NMDA channel blockers in depression

A number of clinical properties of NMDA channel blockers are highly favourable, in comparison to the older antidepressants. Above all, the NMDA channel blockers have a very rapid impact upon depression, within hours, compared to several weeks for the older drugs. The NMDA channel blockers can also impact upon the most stubborn depressions, in which the older drugs, psychotherapy and even ECT proved ineffective and frustrating. Finally, the NMDA channel blockers have a rapid anti-suicidal effect, which as experience accrues, may come to represent a specific indication in acute settings.

The downsides: NMDA channel blockers in depression: Real, potential & hyped

All effective treatments carry a downside in terms of side effects, but in comparison to much older psychiatric therapies such as clozapine, lithium and benzodiazepenes, ketamine/esketamine are remarkably safe. Of course, many patients will be put off by the idea of having psychedelic experiences and there is also a worry over possible diversion, given that ketamine is used as a club drug by people actually seeking those very same psychedelic experiences. Compared to other drugs of abuse however, ketamine addiction is a rare phenomenon, and withdrawal reactions are not recognised. Heavy, unrestrained use of ketamine is known to cause bladder dysfunction, but this appears to be a feature of recreational misuse rather than in the clinic, where bladder function can easily be monitored. 

It has been suggested that ketamine works in the same way as an opiate. Naturally this has led to scare stories, given the recent experience of opiate prescribing in the USA. However, the psychopharmacology of ketamine and opiates are quite different at the behavioural and molecular level. The most serious adverse effect of opiates is respiratory depression and death, because of overstimulation of mu receptors. Ketamine, an NMDA receptor channel blocker, does not cause respiratory depression, and the analgesic effects of ketamine in the CNS do not appear to be mediated via mu opiate receptors. 

Perhaps the major downside of NMDA channel blockers is that the antidepressant effects typically diminish after about one week. With repeated sessions, this can be extended to about three-four weeks. A major challenge for psychopharmacologists is how to extend the duration of the antidepressant effect. In the UK, ketamine treatment for depression has been available at the NHS Warneford hospital in Oxford for about a decade.  Many patients who benefitted from an initial course of intravenous ketamine return for maintenance sessions, in which the gap between sessions is individually tailored. These are patients whose lives were hitherto dominated by depression, and who found no relief from standard approaches. With maintenance treatment, they can enjoy depression free lives. Hopefully, the time-limited nature of the antidepressant effect will eventually be understood and solutions developed.

Esketamine, as an intranasal spray, now offers the possibility of more widespread and perhaps even routine clinical use for many others disabled by clinical depression. Although there are concerns, it should be realised that the prescribing of NMDA channel blockers will take place within a therapeutic relationship in which close attention is paid to how an individual patient responds, the swift recognition of any adverse effects and provision of supportive psychotherapy (and perhaps in time, even a specialised adjuvant psychotherapy). Measures to prevent diversion can be put be put in place.

History Repeats: A new Golden Age of Psychopharmacology

The old tricyclic antidepressants translated into the clinic within three years of the first positive findings in 1957, in what has been termed the Golden age of Psychopharmacology. Aside from the benefits to thousands of individual patients, a new era of neuroscience was initiated, which revealed much of the physiology of serotonin and noradrenaline (Leiberman,, 2015). Over the ensuing decades, the basic science of brainstem derived neuromodulators and monoamine-based therapeutics developed in tandem, leading to the development of safer alternatives, (the SSRIs in 1971). The positive findings with ketamine and esketamine in depression are ushering in a similar scenario. This time of course, the tools of molecular neuroscience are available, so that the pace of discovery should be quicker, and at a much more fundamental level. Already the therapeutic benefits of NMDA channel blockers are being made available for patients whose lives have been dominated by depression. Just as happened for the older antidepressants, refinements will be made over the coming years with the joint efforts of laboratory based pharmacologists and psychiatrists who treat depressed patients. Novel administration regimes, adjuvant psychotherapies, and new candidate molecules targeting other components of glutamate neurotransmission are likely to appear.

Collingridge GL and Bliss TVP (1995) Memories of NMDA receptors and LTP. Trends in Neurosciences18(2): 54–56. DOI: 10.1016/0166-2236(95)80016-U.

DeFelipe J (2006) Brain plasticity and mental processes: Cajal again. Nature Reviews. Neuroscience7(10): 811–817. DOI: 10.1038/nrn2005.

Ingram R, Kang H, Lightman S, et al. (2018) Some distorted thoughts about ketamine as a psychedelic and a novel hypothesis based on NMDA receptor-mediated synaptic plasticity. Neuropharmacology142: 30–40. DOI: 10.1016/j.neuropharm.2018.06.008.

Kandel ER (1998) A new intellectual framework for psychiatry. The American Journal of Psychiatry155(4): 457–469. DOI: 10.1176/ajp.155.4.457.

Lieberman JA (2015) Shrinks: The Untold Story of Psychiatry. New York: Little Brown and Company.

McEwen BS, Bowles NP, Gray JD, et al. (2015) Mechanisms of stress in the brain. Nature Neuroscience18(10): 1353–1363. DOI: 10.1038/nn.4086.

Psychiatric genetics: everything you need to know.

Psychiatric geneticsPsychiatric genetics can be daunting for the non-expert. But it is so important for all mental health researchers and clinicians to have some understanding of where this field is at. Unlike much of the rest of psychiatric research and theory, modern genetics represents a firm foundation of valid and reliable knowledge. That knowledge is slowly unfurling how we think about psychiatric disorders such as ADHD, autism, depression, OCD, substance abuse, schizophrenia and bipolar.

A 2018 paper by Kendler and colleagues is an ideal overview, a straightforward, highly readable account of where things stand in psychiatric genetics, put in a historical context.

It has long been known that psychiatric illness runs in families. The heritability of psychiatric disorders (i.e. the degree of variance in a trait in a population which can be explained by genetics alone; a figure between 0 and 1) ranges from 0.3-0.4 for PTSD and depression, up to 0.7-0.8 for ADHD, autism, schizophrenia and bipolar. (Figure 1. Orange diagonal).

Psychiatric genetics

For the more genetic disorders (ADHD etc.) susceptibility very rarely comes down to one gene. Far more commonly, hundreds of individual genes are involved. Each gene, on its own, carries a tiny, almost negligible effect, at least in clinical if not statistical terms. But when a collection of risk genes is inherited, the chance of developing a psychiatric disorder starts to increase. For experts in psychiatric genetics, this is known as the polygenic risk score (PRS) the summed value of all the individual risk genes. The PRS is an important measure in modern psychiatric genetics.

Another important key-word is pleiotropy. This is when the same gene is involved in more than one psychiatric disorder. Pleiotropy has been recognized in psychiatry for some years. For example, a gene coding for a Ca2+ channel found on neurons, has long been known to constitute risk for a range of psychiatric disorders such as schizophrenia, bipolar, autism and major depression. Such knowledge is increasingly challenging the long-held view that there are discrete, neatly demarcated psychiatric disorders, as is found in the DSM and ICD classification systems.

Genetics researchers are now turning their attention to how a collection of genetic variants that increase the chances for one disorder (the polygenic risk score, PRS) may also increase the risk for other psychiatric disorders. This is pleiotropy at a higher level. The early findings again point to crossover between disorders. Kendler and colleagues elegantly illustrate the headline findings (Figure 1). The light blue squares show the genetic correlation between disorders using the methods of modern molecular genetics. The light orange squares show the genetic correlation between disorders using the more historical methods of family and twin studies.

For the present the main research effort will be to gather and pool more whole genome data from individual patients (and controls). Sample sizes of >100,000 will find more and more gene variants which confer risk for psychiatric disorders. Groups such as the multinational psychiatric genomics consortium (PGC) co-ordinate this task. Data-sets and computing resources are freely available to any researcher. Whether the traditional diagnostic systems collapse completely or remain in a different form cannot be know at present, but with modern molecular genetics, psychiatry is at last on a firm empirical and theoretical ground.

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).