Translated by Rumia Bose
It has been many years since the last of the innovative psychotropic drugs1was released: no new drugs for depression, psychoses, anxiety disorders, autism, ADHD. I refer here to innovative drugs, not just variants of existing drugs. Why is this so?
The current psychotropics work through special systems
Specific nuclei in the brain are important for specific functions of the brain. The visual cortex is important for what you see, the temporal lobe for recognising faces, the motor cortex for controlling voluntary muscles, the hippocampus for memory, the amygdala for emotion and so on. But the brain must also work as a unit. One must not always react to what one sees, emotions should not be sole determinant of how one acts, memories must be combined with your current perceptions. All these separate functions are coordinated by a number of special systems which have some features in common. Small nuclei send out offshoots to all areas of the brain. They are like crisis centres which, working in coordination, can affect, direct and attune functioning everywhere. But, unlike a crisis centre, they perform these coordinating functions constantly, even when there is no crisis. Each of these systems has one neurotransmitter as messenger: serotonine, noradrenaline, dopamine, histamine, acetylcholine or adrenaline. It is through just these neurotransmitters that all the medicines used in psychiatry work. And we have come to have such a thorough understanding of these systems that is a safe bet to say that no new medicines will be discovered that work via these systems.
What about other brain systems?
Do new medicines for psychiatry have to work through these neurotransmitters, these special systems? Are there no other- completely different – options? These have been sought for the past 20 years, and some have been considered very promising. I do not see much in this, and not only because hundreds of investigated substances have been shown not to work. But also because neurotransmitters other than those mentioned above have a different mode of working. They do not work based out of small nuclei, with offshoots to various other parts of the brain, but rather in isolation, locally in different brain areas. There they work in the same way, in the visual cortex for seeing, the temporal lobe for recognising faces, the motor cortex for controlling voluntary muscles, the hippocampus for memory, the amygdala for emotion and so on. Their effect depends on where they are working. When a medicine works via one of these neurotransmitters, then it has a different local effect in each of these brain areas. And taken together, this gives an uncoordinated effect on all kinds of functions all over the brain. Perhaps it will one day be possible to find a medicine which works only in one brain area and therefore only on one function, but that day is still very far away.
Do new medicines for psychiatry have to work through neurotransmitters, the messengers of the neurons? That is unclear. You could imagine them working via genetic processes. That is not such a wild thought, because genetic processes play a role in psychiatric disorders. Or they might work via brain cells other than the neurons, the glial cells for instance. And there are yet more possible modi of action for new medicines for psychiatry, but our knowledge of the involved cells and processes is still so rudimentary that it will take a long time before we can develop substances which work on them.
Fast working psychotherapy does not exist
The objection is often raised about the current drugs that they take so long to really work, a few weeks at minimum. I think however that this is unavoidable. Our brains are flexible but also very robust. Where short term reactions are concerned, brains are flexible. We can react very quickly to all sorts of stimuli from the outside world. But the brain is also constructed in such a way that the most important functions of the organism do not change easily. Some brain functions are therefore very stable. Behavioural therapists are well aware of this. Cognitive behavioural therapy targeting negative thoughts in depression is no mean task. It takes months or more of work to slowly change the habit of seeing problems at every turn. This is because this pattern is ingrained. This ingrained pattern can be described in psychological terms – ingrained thoughts – but you can also describe it at the level of the brain.
Psychotropics that work fast, don’t last
In the course of that process of engraining, millions, even billions of connections are made between millions, billions of neurons which are the basis of the appearance of negative thoughts. The disappearance or alteration of even a large number of these connections will still change nothing about the ingrained negative thoughts. This is because no particular connection or neuron is essential for that function. You could say that all the connections for that function are present in at least twice the required numbers. When someone with a depression has a short relief from his negative thoughts, they soon reappear. Only when that whole circuit of connections and neurons is reconstructed, bit by bit, is someone conclusively relieved of their negative thoughts. And behavioural therapists and psychiatrists know that this is seldom completely achievable. Antidepressants stimulate the transformation of circuits and neurons, but that takes at least weeks and usually months. This means that fast working antidepressants do exist, but that their effect usually does not last.
At the moment (es)ketamine seems like a very promising antidepressant, but it may turn out to be a one-day wonder, working fast but not enduring. Before the current antidepressants were developed, amphetamine was used as an antidepressant with the firm conviction that it worked. It can indeed relieve a depression quickly, but the effect does not endure.
Neither do we have fast working medications for the treatment of schizophrenia, anxiety disorders or autism. The brain circuits are changed with the characteristics of the disorder, just as the brain of each human changes in line with their characteristics. It takes months, years, before these changes can be undone.
Conclusion: no new psychotropics in the near future!
I do not foresee any new medicines for psychiatry coming any day soon2. But there is still a lot of progress to be made in the treatment of depression, psychoses, anxiety disorders, autism, and ADHD. One must understand that pharmacotherapy and psychotherapy can complement and enhance one another, as described above and in “Why people don’t want antidepressants but do want psychotherapy“. Integration of these treatment modalities can be extremely rewarding.
van den Brink RL, Pfeffer T, Donner TH (2019): Brainstem Modulation of Large-Scale Intrinsic Cortical Activity Correlations. Front Hum Neurosci 13. DOI: 10.3389/fnhum.2019.00340
Girgis RR, Zoghbi AW, Javitt DC, Lieberman JA (2018): The past and future of novel, non-dopamine-2 receptor therapeutics for schizophrenia: A critical and comprehensive review. J Psychiatr Res DOI: 10.1016/j.jpsychires.2018.07.006
Ceskova E, Silhan P (2018): Novel treatment options in depression and psychosis. Neuropsychiatr Dis Treat 14:741–747.
Totah NK, Neves RM, Panzeri S, Logothetis NK, Eschenko O (2018): The Locus Coeruleus Is a Complex and Differentiated Neuromodulatory. System Neuron 0. DOI: 10.1016/j.neuron.2018.07.037
Froböse MI, Cools R (2018): Chemical neuromodulation of cognitive control avoidance. Current Opinion in Behavioral Sciences 22:121–127
Shine JM, van den Brink RL, Hernaus D, Nieuwenhuis S, Poldrack RA (2018): Catecholaminergic manipulation alters dynamic network topology across cognitive states. Network Neuroscience 2:381–396.
Ren J, Friedmann D, Xiong J, Liu CD, Ferguson BR, Weerakkody T, et al. (2018): Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems. Cell 0. DOI: 10.1016/j.cell.2018.07.043
Stauffer WR (2018): The biological and behavioral computations that influence dopamine responses. Curr Opin Neurobiol 49:123–131.
Berke JD (2018): What does dopamine mean? Nature Neuroscience 21:787–793.
Yon D, Lange FP de, Press C (2018): The Predictive Brain as a Stubborn Scientist. Trends in Cognitive Sciences 0. DOI: 10.1016/j.tics.2018.10.003
Andrade C (2017): Ketamine for Depression, 1: Clinical Summary of Issues Related to Efficacy, Adverse Effects, and Mechanism of Action. J Clin Psychiatry 78:e415–e419.