SSRI antidepressants normally take a few weeks before any showing mental health benefits, but how come it takes so long? Now a study from a group of clinicians and scientists provides the first human evidence that this is due to physical changes in the brain leading to greater brain plasticity developing over the first few weeks of SSRI intake. This may also begin to explain one of the mechanisms of how antidepressants work. This work has been presented at the ECNP conference in Barcelona on 9th October and is also due to be published (has been accepted) in a peer-reviewed journal. Doctors have been puzzled as to why Selective Serotonin Reuptake Inhibitors (SSRIs) take time before having an effect. Researchers in Copenhagen, Innsbruck and University of Cambridge have undertaken a randomised, double-blind placebo-controlled study in a group of healthy volunteers which shows a gradual difference in how many nerve cell connections (synapses) the brain cells have between those taking the antidepressants and a control group, depending on how long the treatment lasts.
17 volunteers were given a 20mg daily dose of the SSRI escitalopram, with 15 volunteers given a placebo. Between 3 and 5 weeks after starting the trial, their brains were scanned with a PET scanner, which showed the amount of synaptic vesicle glycoprotein 2A in the brain: this is an indicator of the presence of synapses, so the more of the protein is found in an area, the more synapses are present in that area (i.e., greater synaptic density). These scans showed significant between-group differences in how the synapse density evolved over time. Researchers found that with those taking the SSRI, over time there was a gradual increase in synapses in the neocortex and the hippocampus of the brain, compared to those taking placebo. We did not see any effect in those taking placebo.The neocortex takes up around half of the brain’s volume; it is a complex brain structure that deals with higher functions, such as sensory perception, emotion, and cognition. The hippocampus, which is found deep in the brain, functions with memory and learning.
The first study to compare effects of antidepressants with running exercises for anxiety, depression and overall health shows that they have about the same benefits for mental health – but a 16-week course of running over the same period scores higher in terms of physical health improvement, whereas antidepressants lead to a slightly worse physical condition, as has been suggested by previous studies. However, the drop-out rate was much higher in the group which initially chose exercise. The researchers studied 141 patients with depression and/or anxiety. They were offered a choice of treatment; SSRI antidepressants for 16 weeks, or group-based running therapy for 16 weeks. 45 chose antidepressants, with 96 participating in running. The members of the group which chose antidepressants were slightly more depressed than the members of the group that chose running. Treatment with antidepressants required patients to adhere to their prescribed medication intake but this generally does not directly impact on daily behaviors.
In contrast, exercise directly addresses the sedentary lifestyle often found in patients with depressive and anxiety disorders by encouraging persons to go outside, set personal goals, improve their fitness and participate in a group activity. The antidepressant group took the SSRI Escitalopram for 16 weeks. The running group aimed for two to three closely supervised 45-minute group sessions per week (over 16 weeks). The adherence to the protocol was lower in the running group (52%) than in the antidepressant group (82%), despite the initial preference for running over antidepressants. At the end of the trial, around 44% % in both groups showed an improvement in depression and anxiety, however the running group also showed improvements in weight, waist circumference, blood pressure, and heart function, whereas the antidepressant group showed a tendency towards a slight deterioration in these metabolic markers.
Professor Brenda Penninx (Vrije University, Amsterdam) presented the work at the ECNP conference in Barcelona (after recent publication in the Journal of Affective Disorders) saying: “We wanted to compare how exercise or antidepressants affect your general health, not just your mental health This study gave anxious and depressed people a real-life choice, medication or exercise. Interestingly, the majority opted for exercise, which led to the numbers in the running group being larger than in the medication group”.
Professor Knudsen added: “This points towards two main conclusions. Firstly, it indicates that SSRIs increase synaptic density in the brain areas critically involved in depression. This would go some way to indicating that the synaptic density in the brain may be involved in how these antidepressants function, which would give us a target for developing novel drugs against depression. The second point is that our data suggest that synapses build up over a period of weeks, which would explain why the effects of these drugs take time to kick-in”.
Commenting, Dr Eric Ruhe (Amsterdam University Medical Centres) said: “These are very interesting results that again show that physical health can influence mental health and that treatment of depression and anxiety can be achieved by exercising, obviously without the adverse effects of antidepressant drugs. However, several remarks are important. First the patients followed their preference, which is common practice, but ideally we should advise patients what will work best. Following this choice is understandable from a pragmatic point of view when patients have strong preferences, which you have to take into account when doing a study like this. The downside is that the comparisons between groups might be biased compared to doing this in a truly randomized study. For example, patients in the antidepressant group were more depressed which might be associated with less chance of persisting engagement in the exercises. So, we have to be careful not to overinterpret the comparisons between groups, which the authors acknowledge properly. Finally, a very important finding is the difference in adherence between the interventions: 52% in the exercise group and 82% in the antidepressant group. This shows that it is more difficult to change a lifestyle habit than taking a pill. This is not exclusively found in psychiatry, indicating that we also have to focus on how to improve compliance to healthy behavior. This could have tremendous impact on healthcare more generally, but also on psychiatric diseases”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Curr Top Behav Neurosci. 2023; 60:73-87.
Hum Mol Genet. 2021 May 29; 30(10):847-64.
Transl Psychiatry. 2021 Dec; 11(1):622.Â
Front Psychiatry. 2021; 12:698954.