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Why the Thrill is Gone: Scientists Identify Potential Target for Treating Major Symptom of Depression

December 16, 2012 1 comment

Stanford University School of Medicine scientists have laid bare a novel molecular mechanism responsible for the most important symptom of major depression: anhedonia, the loss of the ability to experience pleasure. While their study was conducted in mice, the brain circuit involved in this newly elucidated pathway is largely identical between rodents and humans, upping the odds that the findings point toward new therapies for depression and other disorders.

Additionally, opinion leaders hailed the study’s inventive methodology, saying it may offer a much sounder approach to testing new antidepressants than the methods now routinely used by drug developers.

While as many as one in six Americans is likely to suffer a major depression in their lifetimes, current medications either are inadequate or eventually stop working in as many as 50 percent of those for whom they’re prescribed.

“This may be because all current medications for depression work via the same mechanisms,” said Robert Malenka, MD, PhD, the Nancy Friend Pritzker Professor in Psychiatry and Behavioral Sciences. “They increase levels of one or another of two small molecules that some nerve cells in the brain use to signal one another. To get better treatments, there’s a great need to understand in greater detail the brain biology that underlies depression’s symptoms.” The study’s first author is Byung Kook Lim, PhD, a postdoctoral scholar in Malenka’s laboratory.

Malenka is senior author of the new study, published July 12 in Nature, which reveals a novel drug target by showing how a hormone known to affect appetite turns off the brain’s ability to experience pleasure when an animal is stressed. This hormone, melanocortin, signals to an ancient and almost universal apparatus deep in the brain called the reward circuit, which has evolved to guide animals toward resources, behaviors and environments — such as food, sex and warmth — that enhance their prospects for survival.

Scientists found that both chronic stress and the direct administration of melanocortin diminished the signaling strength of some synapses in the nucleus accumbens that contain receptors for melanocortin. The nucleus accumbens is labeled in this drawing of a human brain cross section. (up)

“This is the first study to suggest that we should look at the role of melanocortin in depression-related syndromes,” said Eric Nestler, MD, PhD, professor and chair of neuroscience and director of the Friedman Brain Institute at Mount Sinai School of Medicine in New York. Nestler was not involved in the study but is familiar with its contents. Read more…

Ketamine for Depression: Yay or Neigh?

December 14, 2010 Leave a comment

Venn diagram of psychoactive drugs (up)

 

NOTE: This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic drugs: implications for the treatment of mood disorders, by Franz Vollenweider & Michael Kometer. This article will be freely available, with registration, until September 23. For more information on this Blog Focus, see the Table of Contents.

 

Veterinary Anesthetic, Club Drug, or Antidepressant?
Club drug “Special K” (aka ketamine) is stepping out of the laser light into the broad daylight of mainstream psychiatry with the publication of a new review article by Vollenweider and Kometer (2010). Long used to anesthetize animals (and children), ketamine was classified as a “dissociative anesthetic” by Domino et al. (1965) for its combined effects of sedation/analgesia and hallucinations. Domino (2010) recently revisited his classic paper, which reported on a study in 20 volunteers incarcerated at the Jackson Prison in Michigan:

The first human was given ketamine in an intravenous subanesthetic dose on August 3, 1964. Guenter [Corssen, M.D.] and I gradually increased the dose from no effect, to conscious but “spaced out,” and finally to enough for general anesthesia. Our findings were remarkable! The overall incidence of side effects was about one out of three volunteers. Frank emergence delirium was minimal. Most of our subjects described strange experiences like a feeling of floating in outer space and having no feeling in their arms or legs.

The ego death of the “K hole” can be a terrifying experience for some (“I ceased to exist”) or transformative for others (“I witnessed myself as a part of the universal collective of strange energy”)1. In their Nature Reviews Neuroscience opinion piece, Vollenweider and Kometer considered ketamine a psychedelic, along with the traditional hallucinogens such as LSD, psilocybin, and mescaline. They noted that both classes of drugs may have psychotherapeutic effects through actions on the excitatory glutamate neurotransmitter system.

Ketamine is an antagonist of the glutamate NMDA receptor and is thought to work by blocking NMDA receptors on inhibitory GABA-containing interneurons, ultimately promoting glutamate release. In a scientific tour de force, Li and colleagues (2010) demonstrated that the mTOR (mammalian target of rapamycin) protein kinase pathway is rapidly activated by ketamine. This sets off a cascade of events including the formation of new synapses on dendritic spines. Using a combination of cellular, molecular, electrophysiological, behavioral, and phamacological techniques, ketamine was shown to exhibit antidepressant properties in animal models of depression and anxiety, perhaps via rapid induction of synaptic plasticity in the medial prefrontal cortex (PFC). Regions of the medial PFC in humans, particularly the ventral anterior cingulate cortex, have been implicated in the pathophysiology of major depression.

Human clinical trials of ketamine as a rapidly acting antidepressant aren’t especially new. A randomized, double-blind study in 2000 involved administration of saline or a single subanesthetic dose of ketamine (0.5 mg/kg intraveneously) to nine depressed patients, seven of whom completed the trial (Berman et al., 2000). Within 72 hrs, amelioration of depressive symptoms was observed. Half of the treated patients showed a 50% or greater improvement in depression scores. However, these therapeutic effects weren’t very long-lasting, returning to baseline levels in 1-2 weeks. In a larger study, 18 patients with major depression participated in a similar double-blind cross-over design where they received the 0.5 mg/kg dose of ketamine and placebo one week apart (Zarate et al., 2006). The patients were rated at baseline and at 40, 80, 110, and 230 minutes and 1, 2, 3, and 7 days post-infusion on a number of clinical scales, including the Hamilton Depression Rating Scale (HDRS), the Brief Psychiatric Rating Scale (BPRS) positive symptoms subscale, and the Young Mania Rating Scale (YMRS).

The primary outcome measure was change in HDRS score, shown in Figure 2 below (top graph). Significant improvements began at the 110 min time point. Scores declined further from 1-3 days and remained below placebo levels for 7 days. However, unusual experiences were noted at 40 min, with substantial increases in scores for psychosis-like and mania-like symptoms. Other adverse events associated with ketamine included…

…perceptual disturbances, confusion, elevations in blood pressure, euphoria, dizziness, and increased libido. … The majority of these adverse effects ceased within 80 minutes after the infusion. In no case did euphoria [YMRS] or derealization/depersonalization [BPRS] persist beyond 110 minutes (Figure 2, middle and bottom graphs).


Figure 2 (Zarate et al., 2006). Change in the 21-item HDRS, BPRS positive symptoms subscale, and YMRS scores over 1 week (n=18). Values are expressed as generalized least squares means and standard errors for the completer analysis. * indicates P<.05; †, P<.01; ‡, P<.001.

 

So here we have several research groups that say yay! to ketamine as an antidepressant. Are there any naysayers?

Although the immediate onset of symptom amelioration gives ketamine a substantial advantage over traditional antidepressants (which take 4-6 weeks to work), there are definite limitations (Tsai, 2007). Drawbacks include the possibility of ketamine-induced psychosis (Javitt, 2010), limited duration of effectiveness (aan het Rot et al., 2010), potential long-term deleterious effects such as white matter abnormalities (Liao et al., 2010), and an inability to truly blind the ketamine condition due to obvious dissociative effects in many participants.

At present, what are the most promising uses for ketamine as a fast-acting antidepressant? Given the disadvantages discussed above, short-term use for immediate relief of life-threatening or end-of-life depressive symptoms seem to be the best indications.

Suicidal Ideation
Acute ketamine treatment in suicidal patients presenting at the ER has the potential to provide immediate changes in the risk that a patient will harm herself when released, when accompanied by proper followup and appropriate long-term treatment. An open label study in 33 patients with refractory depression involved infusion of 0.5 mg/kg ketamine over a period of 40 min (DiazGranados et al., 2010). Those with high scores on the Scale for Suicide Ideation showed significant improvements at 40 min that were maintained for the 230 min duration of the study. Obviously, one would like to follow actively suicidal patients for a longer period of time than 4 hrs, and future clinical trials should take this into account.

Palliative Care
Watching a terminally ill loved one suffer from unbearably excruciating pain is one of the most emotionally wrenching experiences you’ll ever have. Anything, and I mean anything , that will relieve this sort of suffering should be freely administered without reservation or stigma. As discussed in The secret history of psychedelic psychiatry, psilocybin has been shown to alleviate anxiety and pain in cancer patients. Reports of psychedelic psychotherapy in the 60s and 70s suggested that many patients overcame their fear of death through LSD-facilitated sessions. More recently, an open label study in two hospice patients, each with a prognosis of only weeks or months to live, showed beneficial effects of ketamine in the treatment of anxiety and depression (Irwin & Iglewicz, 2010). A single oral dose produced rapid improvement of symptoms and improved end of life quality. To disentangle the pain relieving and antidepressant effects of ketamine, the authors emphasized the importance of conducting clinical trials for this particular indication.

Better Drugs for a Brighter Tomorrow
Newer NMDA antagonist drugs with fewer dissociative side effects (e.g., more selective antagonists such as NR2B receptor blocker EVT 101) are undergoing testing and development. Personalized medicine and pharmacogenomics may ultimately shift psychedelic experiences out of the realm of hippies and into the doctor’s arsenal.

 

References

aan het Rot M, Collins KA, Murrough JW, Perez AM, Reich DL, Charney DS, Mathew SJ. (2010). Safety and efficacy of repeated-dose intravenous ketamine for treatment-resistant depression. Biol Psychiatry 67:139-45.

Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, Krystal JH. (2000). Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351-4.

DiazGranados N, Ibrahim LA, Brutsche NE, Ameli R, Henter ID, Luckenbaugh DA, Machado-Vieira R, Zarate CA Jr. (2010). Rapid resolution of suicidal ideation after a single infusion of an N-methyl-D-aspartate antagonist in patients with treatment-resistant major depressive disorder. J Clin Psychiatry. Jul 13. [Epub ahead of print]

Domino EF. (2010). Taming the ketamine tiger. Anesthesiology 113:678-84.

Domino EF, Chodoff P, Corssen G. (1965). Pharmacologic Effects of CI-581, a New Dissociative Anesthetic, in Man. Clin Pharmacol Ther. 6:279-91.

Irwin SA, Iglewicz A. (2010). Oral ketamine for the rapid treatment of depression and anxiety in patients receiving hospice care. J Palliat Med. 13:903-8.

Javitt DC. (2010). Glutamatergic theories of schizophrenia. Isr J Psychiatry Relat Sci. 47:4-16.

Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G, Duman RS. (2010). mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329(5994):959-64.

Liao Y, Tang J, Ma M, Wu Z, Yang M, Wang X, Liu T, Chen X, Fletcher PC, Hao W. (2010). Frontal white matter abnormalities following chronic ketamine use: a diffusion tensor imaging study. Brain 133:2115-22.

Tsai GE. (2007). Searching for rational anti N-methyl-D-aspartate treatment for depression. Arch Gen Psychiatry 64:1099-100; author reply 1100-1.

Vollenweider, F., & Kometer, M. (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders Nature Reviews Neuroscience, 11 (9), 642-651 DOI: 10.1038/nrn2884

Zarate CA Jr, Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, Charney DS, Manji HK. (2006). A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 63:856-64.

Serotonin, Psychedelics and Depression

December 13, 2010 Leave a comment

Note: This post is part of a Nature Blog Focus on hallucinogenic drugs in medicine and mental health, inspired by a recent Nature Reviews Neuroscience paper, The neurobiology of psychedelic drugs: implications for the treatment of mood disorders, by Franz Vollenweider & Michael Kometer. That article will be available, free (once you register), until September 23. For more information on this Blog Focus, see the “Table of Contents” here.

 
Ketamine, an anesthetic with hallucinogenic properties, which is attracting a lot of interest at the moment as a treatment for depression.

Ketamine, however, is not a “classical” psychedelic like the drugs that gave the 60s its unique flavor and left us with psychedelic rock, acid house and colorful artwork. Classical psychedelics are the focus of this post.

The best known are LSD (“acid”), mescaline, found in the peyote and a few other species of cactus, and psilocybin, from “magic” mushrooms of the Psilocybe genus. Yet there are literally hundreds of related compounds. Most of them are described in loving detail in the two heroic epics of psychopharmacology, PIKHaL and TIKHaL, written by chemists and trip veterans Alexander and Ann Shulgin.

The chemistry of psychedelics is closely linked with that of depression and antidepressants. All classical psychedelics are 5HT2A receptor agonists. Most of them have other effects on the brain as well, which contribute to the unique effects of each drug, but 5HT2A agonism is what they all have in common.

5HT2A receptors are excitatory receptors expressed throughout the brain, and are especially dense in the key pyramidal cells of the cerebral cortex. They’re normally activated by serotonin (5HT), which is the neurotransmitter that’s most often thought of as being implicated in depression. The relationship between 5HT and mood is very complicated, and depression isn’t simply a disorder of “low serotonin”, but there’s strong evidence that it is involved.

There’s one messy detail, which is that not quite all 5HT2A agonists are hallucinogenic. Lisuride, a drug used in Parkinson’s disease, is closely related to LSD, and is a strong 5HT2A agonist, but it has no psychedelic effects. It’s recently been shown that LSD and lisuride have different molecular effects on cortical cells, even though they act on the same receptor – in other words, there’s more to 5HT2A than simply turning it “on” and “off”.

How could psychedelics help to treat mental illness? On the face of it, the acute effects of these drugs – hallucinations, altered thought processes and emotions – sound rather like the symptoms of mental illness themselves, and indeed psychedelics have been referred to as “psychotomimetic” – mimicking psychosis.

There are two schools of thought here: psychological and neurobiological.

The psychological approach ruled the first wave of psychedelic psychiatry, in the 50s and 60s. Psychiatry, especially in America, was dominated by Freudian theories of the unconscious. On this view, mental illness was a product of conflicts between unconscious desires and the conscious mind. The symptoms experienced by a particular patient were distressing, of course, but they also provided clues to the nature of their unconscious troubles.

It was tempting to see the action of psychedelics as a weakening of the filters which kept the unconscious, unconscious – allowing repressed material to come into awareness. The only other time this happened, according to Freud, was during dreams. That’s why Freud famously called the interpretation of dreams the “royal road to the unconscious”.

Psychedelics offered analysts the tantalizing prospect of confronting the unconscious face-to-face, while awake, instead of having to rely on the patient’s memory of their previous dreams. To enthusiastic Freudians, this promised to revolutionize therapy, in the same way that the x-ray had done so much for surgery. The “dreamlike” nature of many aspects of the psychedelic experience seemed to confirm this.

Not all psychedelic therapists were orthodox Freudians, however. There were plenty of other theories in circulation, many of them inspired by the theorists’ own drug experiences. Stanislav Grof, Timothy Leary and others saw the psychedelic state of consciousness as the key to attaining spiritual, philosophical and even mystical insights, whether one was “ill” or “healthy” – and indeed, they often said that mental “illness” was itself a potential source of spiritual growth.

Like many things, psychiatry has changed since the 60s. Psychotherapy is currently dominated by cognitive-behavioural (CBT) theory, and Freudian ideas have gone distinctly out of fashion. It remains to be seen what CBT would make of LSD, but the basic idea – that carefully controlled use of drugs could help patients to “break through” psychological barriers to treatment – seems likely to remain at the heart of their continued use.

The other view is that these drugs could have direct biological effects which lead to improvements in mood. Repeated use of LSD, for example, has been shown to rapidly induce down-regulation of 5HT2A receptors. Presumably, this is the brain’s way of “compensating” for prolonged 5HT2A activation. This is probably why tolerance to the effects of psychedelics rapidly develops, something that’s long been known (and regretted) by heavy users.

Vollenweider and Kometeris note that this is interesting, because 5HT2A blockers are used as antidepressants – the drugs nefazadone and mirtazapine are the best known today, but most of the older tricyclic antidepressants are also 5HT2A antagonists. Atypical antipsychotics, which are also used in depression, are potent 5HT2A antagonists as well.

So indirectly suppressing 5HT2A might be one biological mechanism by which psychedelics improve mood. However, questions remain about how far this could explain any therapeutic effects of these drugs. Psychedelic-induced 5HT2A down-regulation is presumably temporary – and if all we need to do is to knock out 5HT2A, it would surely be easiest to just use an antagonist…

 

Reference:

Vollenweider FX, & Kometer M (2010). The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nature Reviews Neuroscience, 11 (9), 642-51 PMID: 20717121