Monthly Archives: December 2012

New treatments for schizophrenia?

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The 1st generation anti-psychotics

It is sometimes said that all the treatments in psychiatry were discovered by chance (or serendipity, to use the technical term), rather than by planning. This is not strictly true. In fact many of our treatments for schizophrenia were discovered by design. The rationale was to start with a molecule which could induce a transient psychosis, even in healthy people – a molecule like amphetamine or LSD.

Thereafter the task was to find a drug which could block the effects of the psychosis-inducing compound. Such a drug, it was reasoned, could be an effective medicine for schizophrenia.

A Belgian researcher called Paul Janssen used this approach to great effect. He observed the effects of amphetamine in professional cyclists, who were using the drug to combat fatigue. Many of the cyclists developed an acute psychosis which was identical to paranoid schizophrenia. Janssen was the owner of a private research facility and was in an ideal position to search for medicines which could block amphetamine.

Progress was rapid and the compound haloperidol was discovered. And it turned out that haloperidol was a highly effective medicine for schizophrenic psychoses. Used in small doses, without interruption, haloperidol is a powerful treatment against hallucinations, delusions and agitation. But high doses are best avoided, as they can cause movement disorder.

The 2nd generation anti-psychotics

With this success of haloperidol, attention focused on other psychosis inducing drugs. This time LSD was taken as the psychosis-inducing agent. Numerous reports had shown that LSD (or 'acid') could transform consciousness in a way which was similar to the experience of people with schizophrenia. What was needed was a compound to block LSD, followed by a trial of the new compound in people with schizophrenia. Again the approach worked, giving us the medicine risperidone.

Olanzapine, sertindole, quetiapine and others followed. This class of anti-psychotic has become the first-line treatment in many countries and carries much less propensity to cause movement disorder as a side effect. However, careful attention is needed to avoid problems of weight gain and high cholesterol. Haloperidol acts on the dopamine system whereas second generation anti-psychotics like risperidone work on dopamine, but also target another brain transmitter called serotonin.

The next generation anti-psychotics

Two other drugs of abuse are associated with psychotic reactions. The first of these is ketamine, which has become popular on the club scene. Ketamine can elicit bizarre changes in consciousness which resemble the picture of schizophrenic psychosis. Ketamine can also induce the so-called negative symptoms. (Apathy, loss of drive and a reduced capacity for emotions, along with a rigid, concrete style of thinking).

The glutamate NMDA channel. Ketamine blocks the channel. Drugs which counteract ketamine may be useful antipsychotic medicines.

 

Ketamine works on the glutamate signalling system. As before the task was to find a compound which blocked the effects of ketamine. This has now been done, and in fact there are several different types of molecule available (Bitopertin, AMG747).

Now the challenge is to assess if any of these new compounds are good treatments for schizophrenia. At this time, several clinical trials in schizophrenic patients are underway, including some at The Institute of Psychiatry in London.

The other promising lead involves compounds which can block the effects of cannabis. About a dozen recent studies have shown that repeated use of cannabis is a risk factor for the development of schizophrenia. Skunk cannabis is known to be particularly hazardous for mental health. (Skunk contains high THC).

THC acts at cannabinoid receptors. Drugs which block the effects of THC are showing promise as medicines for schizophrenia.

 

Our research group and others have shown that a natural molecule called CBD can oppose the effects of THC in humans. CBD therefore becomes a candidate anti-psychotic medicine. Already one trial in Germany has found CBD to be as effective as a second generation anti-psychotic in people with schizophrenia. A number of larger studies are now underway. For an svg image click here.

 

Summary

There is an ongoing search for new medicines in schizophrenia. The first compounds such as haloperidol led to a fundamental change in psychiatric practice. The second generation medicines 'solved' the problem of motor side-effects, but at the cost of obesity and other metabolic complications. Hopefully a new generation of effective anti-psychotics will emerge in the next few years. Like their predecessors, the roots of their development may well be in design rather than by chance.

 

New insights into how antidepressants work.

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fMRI scan.

It is well established that antidepressants take at least 2 weeks to shift a depressed mood. A new study from researchers at Oxford, reveals that the drug is working behind the scenes, much earlier than this.

People with depression are known to show an exaggerated response to pictures of human faces that are expressing fear. The response can be observed using functional MRI brain scanning. The part of the brain which lights up is their own 'fear processor', the amygdala. The usual interpretation is that the depressed patient's fear system is unduly sensitive to anything from the outside world which signifies fear. And human faces elicit the most robust response.

Previous work had shown that standard SSRI antidepressants can dampen down the hyperactive amygdala, and return it's function to normal. What was unknown was whether the effect on the amygdala or the effect on mood came first.

The Oxford researchers have now shown that SSRI antidepressants dampen down the amygdala at least 1 week before the patient experiences a shift in their mood. They compared 3 groups of people: depressed patients who had been randomised to receive escitalopram (10mg); depressed patients who had been randomised to placebo; and a group of healthy controls. A week after being randomised to active drug or placebo, the depressed patients were given an fMRI scan.

The main finding was that the patients who had been taking escitalopram for a week had normal amygdala responses to pictures of fearful human faces. In contrast, the patients on placebo showed the characteristic hyperactive response in the amygdala on the right hand-side of their brains (see scan above). Notably, 1 week was too early for any antidepressant effect – Treated and untreated patients were equally depressed at this stage.

This is an important finding, which shows that SSRI antidepressants affect how the brain processes emotional information before the patient feels an improvement in their mood.

Further studies are planned. One key goal will be to assess if the degree of amygdala dampening at 1 week can distinguish between patients who ultimately get better from those who will remain depressed. The technology might even be used in selecting the 'best' type of antidepressant drug for a particular patient, rather than having to adopt a 'wait and see' approach.

The full paper can be read here

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3488813/

 

Is cannabis addictive?

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For many years it was assumed that cannabis was not an addictive substance. This view was based on the apparent lack of a cannabis withdrawal syndrome. The absence of a withdrawal syndrome was said to distinguish cannabis from ‘hard drugs’, such as opiates and cocaine, and even from the two most widely used ‘soft drugs’, nicotine and alcohol.

Recently a number of studies have established that a cannabis withdrawal syndrome does indeed exist. In the latest of these, 49 users agreed to try a 2-week cannabis free period.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0044864

As in previous work, participants reported a number of symptoms during abstinence. Symptoms included difficulty sleeping, anxiety, mood swings, physical tension, stomach pain and craving. Symptoms peaked at around 4 days and then gradually decreased over the next 10 days. 

Notably, those who experienced the most severe withdrawal symptoms were more likely to relapse and begin taking cannabis again. They also experienced more functional impairment during abstinence. 

This study highlights the difficulties people can experience when they attempt to give up cannabis. It also demonstrates that the withdrawal reaction is an important factor in determining whether an attempt at abstinence is likely to be successful. 

 

 

N-acetylcysteine: Effective in bipolar depression?

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N-acetylcysteine (NAC) is a derivative of the naturally occurring amino-acid cysteine. Many people use it as a nutritional supplement, but NAC also has clear pharmacological properties. By far the most important role of NAC is as an ‘antidote’ in cases of paracetamol overdose. In this role, it can be life-saving.

However, the properties of NAC may extend beyond the emergency room. Recent research from Australia suggests it might be effective in the depressive phase of bipolar disorder. http://www.scielo.br/pdf/rbp/v33n4/v33n4a11.pdf

Larger studies are needed, but if the initial promise holds true, this would represent an important advance. In bipolar disorder, the depressive phase can be extremely difficult to shift, although conventional pharmacology has also made some significant inroads in the past few years. http://journals.psychiatryonline.org/data/Journals/AJP/4013/1351.pdf

 

Major Depression: What is currently known?

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“About one in five people will suffer from major depression at some point in their lives. Aside from the psychological burden, people suffering from depression are known to be at higher risk of heart disease”.

But what are the causes of depression? What happens in the brain when someone is depressed? And which treatments work best?

Writing in the Lancet, Phillips and colleagues from the University of Pittsburgh give an authoritative account of the current state of the art. They appraise the evidence for antidepressant drugs and psychological therapies, and highlight promising new treatment strategies.

Kupfer DJ, Frank E & Phillips ML (2012) Major depressive disorder: new clinical, neurobiological and treatment perspectives. Lancet 379:1045-55.

The full article is available at:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3397431/