The Future

Professor Arvid Carlsson, Nobel Prize Laureate 2000, shares some of his thoughts on the future of antidepressant and antipsychotic research.

Long way back

Some of the prominent challenges in antidepressant research are how to improve the potency and onset of action of the SSRIs. However, I am afraid that the very nature of depression will limit the possibility of success in these areas.

It is inherent in depression that you have processes ongoing in the brain, they take time, they are slow. So that just as depression develops slowly over months, depending, according to my speculation, on a very complex chain of events in the brain that involve long-term activities like the synthesis of proteins, changes in complex neurocircuitries, then if you want to turn it back, you have to go the same long way back. For example, consider that none of the various forms of antidepressant treatments so far, including the MAOIs, TCAs or SSRIs offer immediate antidepressant effect.

The chronic nature of depression also underscores the importance of not stopping antidepressant treatment prematurely. Thankfully, there is now some awareness among doctors not to stop treatment too early and risk relapse and suicides. The suicide rate in Sweden dropped 25 % when the SSRIs were introduced here.

Beyond the dopamine theory

This complexity in neurocircuitries is also expressed in psychoses. There is no doubt that we must move beyond the dopamine theory of psychosis and identify the other important players like serotonin and glutamate and how they interact with each other.

Certainly one should try to see if simultaneous attacks on different receptors can be more powerful and we could start by combining the different rather selective drugs that came out of rationale drug design to see if combination treatments can be found.

The new generation of antipsychotic agents like risperidone and olanzapine have an effect on serotonin receptors, especially 5-HT_2A, which seems to be particularly important. I would not be surprised if some anti-alpha-adrenergic action could also be useful, which is also present in these drugs. But we need better tools to analyze why the new antipsychotia have led to small, but significant, improvements in efficacy.

Carlsson Research

Today, I am facing the challenges that lay ahead in the field of antipsychotic development from the offices of Carlsson Research, a drug discovery company founded two years ago by myself and eleven other academic researchers, including my daughter Maria Carlsson. Since getting an infusion of funding in March 2000, the company has been able to make significant headway in our current objective, which is to develop mild dopaminergic stabilisers.

Our philosophy is a bit different from that espoused by much of the rest of the industry. In fact, I think that the way that high throughput screening is being used today to identify drug candidates with strong binding affinity is not useful because it tends to miss promising compounds that bind only slightly or not at all to receptor sites.

Stabilise the receptor

Rather than stimulating or blocking the receptor, the goal should be to stabilise it. I know that this sounds mysterious, but think about receptor populations like D2 that are not homogenous. We now know that some subpopulations of the total D2 population are functionally opposite to each other. If you stimulate the autoreceptors, for example, you inhibit dopamine, whereas if you stimulate the post synaptic receptors, you get stimulation of dopamine function so there are balances within a certain population of receptors.

If you can find molecules that will occupy the different subpopulations in certain proportions as to not change the balance, to keep it at a normal level, then you could have the possibility of stabilising, preventing hyper- or hypoactivity without changing the baseline.

Knock out the system

The problem with current antipsychotic agents is that they knock out the whole system with all the terrible consequences that follow like causing the reward system to stop functioning and then there is nothing left and life is not worthwhile anymore. This is unfortunately how many people taking these drugs feel today.

Look at the long term effects of blocking receptors with neuroleptics. The brain doesn't like it at all and you end up with tardive dyskinesias. The same occurs when you treat Parkinson's disease with L-dopa, which is a full agonist with poor pharmacokinetic properties. You hit the receptors very hard and have all kinds of problems like dyskinesias induced by the treatment.

The nature of neurotransmitters

After a life-time's work in this field, I have some theories about the various neurotransmitter systems. For instance, our work in the area of schizophrenia has led to the dopamine hypothesis of arousal and I also believe that there is a serotonin hypothesis of both mood elevation and wakefulness.

Although it is not yet well founded, my intuition tells me that there is one serotonergic system that promotes sleep and another that promotes arousal. That would explain why some people have difficulty sleeping while taking SSRIs and others get very sleepy. Also genetics could play a role whereby those who tend to have a poor sleep inducing serotonergic system are more vulnerable to this side effect of SSRI treatment.

Bright future for SSRIs

One thing is sure, given the complexity of the serotonin system, the SSRIs have a bright future ahead of them with many new therapeutic applications in areas such as anxiety and especially obsessive-compulsive disorders. OCD has been so difficult to treat and now there is some progress thanks to the SSRIs.

Understanding the nature of the noradrenaline system has proven more difficult, but certainly there is a noradrenaline hypothesis of depression as well. Clearly, serotonin, dopamine and noradrenaline have an interplay that is important in psychopharmacology.

As for glutamate, well that is the working horse of the brain and so enormously important. Everything that we do is done by means of glutamate and the other neurotransmitters are there to modulate glutamate.

Psychomotor stimulant

Carlsson Research has been using the psychomotor stimulant, MK801, which is an NMDA receptor antagonist, as a tool for investigating glutamate interaction with other neurotransmitters. And we have gotten a lot of mileage out of this compound.

Our work with MK801 shows that psychomotor activity can be controlled independently of dopamine and that there are several different neurotransmitter pathways that go into the striatum and operate in opposite directions. Some of them will elevate arousal and others will have the opposite effect. It may be a complex imbalance that we are dealing with in schizophrenia.

Drugs, behaviour and the future

Carlsson Research's methodology for finding compounds is based on behavioural analysis. We record different components of animal behaviour and then apply multivariate analysis to detect changes in patterns of behaviour, even subtle ones that only the computer can pick up, in animals treated with experimental compounds. If one can replicate a pattern of deviation by means of a drug with a known site of action, this could very well lead to better animal models in psychopharmacology.

And so, in this manner, we plan to keep on working here in Gothenburg, Sweden, to continue changing attitudes in psychopharmacology towards a more enlightened approach to drug development and, ultimately, to be able to turn the truths that we discover in the brain's pharmacology into tangible benefits for patients suffering from mental disorders.