How Antidepressants Work
A brief review of our rapidly expanding knowledge of the mode of action of antidepressants.
(This article was first published by the Lundbeck Institute in the Institute Magazine no. 6, 2003.)
One of the best known medical illustrations from recent years and one used by many of us to explain to patients how their antidepressants work, is the image of the synaptic cleft.
This simple illustration, usually with serotonin receptors and re-uptake pump, has probably done more to explain and legitimise the diagnosis and treatment of depressive illness than any other single initiative in the last twenty years. Most patients find its simple logic reassuring and it seems that doctors do also.
A recent informal survey of colleagues showed that most of us know little more of the mode of action of antidepressants than is illustrated by the diagram.
A typical synaptic cleft diagram used to illustrate the mode of action of antidepressants
Breaks down on closer examination
On closer examination this simple model starts to break down. It does not explain a number of very basic facts the most obvious one being; Why is there a significant delay between starting medication and the onset of symptom relief?
The origins of the model are interwoven with the history of antidepressants. In 1948 Hafliger synthesized imipramine and ten years later Kuhn observed and published its antidepressant properties. In 1965 Schildkraut published what has become known as the Biogenic Amine hypothesis, which postulated that reduced norepinephrine levels were associated with depression.
In the same year Bunney and Davis reviewed "Norepinephrine in depressive reactions" in the Archives of General Psychiatry (ref. 1).
Serotonin was linked to depression in 1965 when Coppen and others postulated serotonin's involvement in depressive illness in the British Journal of Psychiatry (ref. 2)
Axelrod's Nobel Prize
Julius Axelrod investigated the presence of catecholamines in neurons and the phenomenon of release and reuptake (the norepinephrine uptake pump). This research explained the mode of action of imipramine at a molecular level within the synaptic cleft and, together with Katz and von Euler, he received the 1970 Nobel Prize for this work.
His diagram is the origin of the multiple stylised versions we have become familiar with over the last twenty years. In an attempt to integrate the independent observations that both norepinephrine and serotonin were implicated in causing depression.
Arthur Prange formulated the Permissive Biogenic Amine theory. Writing in the Archives of General Psychiatry in 1974 (ref. 3) he postulated that alterations in mood were due to a deficit of serotonin plus either a deficit or excess of norepinephrine. This dual neurotransmitter approach lives on today in the debate as to whether single or dual uptake blockers are more effective in treating depression.
At a molecular level Prange's model focused on the synaptic cleft and this was to remain the area of interest for a number of years.
It appeared self-evident that increasing the availability of serotonin in the synaptic cleft and thus on the post-synaptic receptors changed membrane electrical activity (firing rate) of post-synaptic neurons. This changed firing rate somehow reversed the problems caused by the depression and returned the activity of the "faulty" system to normal.
As noted above this concept did not explain the fact that even though inter-synaptic transmitter levels increased within hours of starting antidepressants, reduction of symptoms did not commence for one or two weeks.
A further clue
A further clue to what was really happening came from the discovery that the neurons of depressed patients had up regulation (increased numbers) of serotonin and norepinephrine receptors and down regulation of uptake pumps (ref. 4). Researchers noted that the onset of antidepressant action did not occur until there was a reduction in the (previously increased) number of post-synaptic receptors and that this down regulation took one to two weeks following the commencement of antidepressants.
These observations suggested there was more to the mechanism of antidepressant action than simply increasing serotonin availability and altering post-synaptic firing rate. As technology advanced it became possible to examine these phenomena and the outcomes of those investigations are set to change forever the way we think about depression and antidepressants.
Neurotrophic factors are substances produced in the brain that act to promote proliferation and plasticity of neurons. In September 1995, Smith and others demonstrated that stress and antidepressants had opposite effects on the production of neurotrophic factors in the locus coeruleus of rat brains (ref. 5).
The implication was that by increasing the production of neurotrophic factors antidepressants might influence the growth, plasticity and survival of neurons. Two months later Nibuya and others published data showing that antidepressants and ECT increased brain derived neurotrophic factor (BDNF) and its receptor (trkB) in the frontal cortex, hippocampus and dentate gyrus of rat brains (ref. 6).
Both these papers noted that the effects on trophic factors were seen only with prolonged (as opposed to acute) use of antidepressants. One interesting difference in findings was that Smith's positive results were confined to agents blocking norepinephrine while Nibuya demonstrated similar results with a number of medications including SSRI's and MAOI's.
Stress and depression
Nineteen months later in July 1997 Dunman and others published "A molecular and cellular theory of depression" (ref. 7) in which they postulated that "stress and other types of neuronal insult can lead to depression in vulnerable individuals" and that there was a "decreased volume of certain brain structures" in individuals with depression.
They concluded, "The therapeutic actions of antidepressant treatments occur via intra cellular mechanisms that increase neurotropic factors necessary for the survival and function of particular neurons."
The relationship between "stress", "vulnerable individuals" and the development of symptoms of depression was further illuminated by Kendler and others who studied female twins for a total of 92,521 person months over 9 years (ref. 8). They considered "genetic risk" and "environmental stress" as risk factors and estimated genetic risk on the family history of depressive illness.
Kendler concluded that there was a relationship between stress and the onset of depression and that the strength of this relationship declined with (a) the number of previous episodes of depression and (b) the magnitude of the genetic risk. Vulnerable individuals were those with a strong family history or with previous episodes of depression. Those with both risk factors were the most vulnerable and were likely to experience depressive episodes "without major environmental stressors".
In the last five years there have been many studies looking at the relationship between stress and/or depression and reduced volume of various brain regions. The hippocampus and prefrontal cortex have been areas of particular interest. There seems little doubt that depres- sive illness, especially chronic major depression leads to loss of neurons and glial cells plus macroscopic atrophy of discrete brain regions. It should be noted that there is a possibility that both the depression and the atrophy could be outcomes of some (as yet) unidentified third process.
Chronic antidepressant use
The intracellular consequences of chronic antidepressant use have been further clarified and reviewed by Yildiz and others (ref. 9). This review examined the network of intracellular events that culminates with increased plasticity ("alterations in dendritic function, synaptic remodelling, long term potentiation, axonal sprouting, neurite extension, synaptogenesis and even neurogenesis.") and postulated two main mechanisms by which norepinephrine and serotonin influence intracellular events.
5HT binds to its receptor and changes the intracellular configuration of the receptor so that G protein can bind to the intracellular receptor site
According to Yildiz all norepinephrine and all serotonin receptors except 5HT3 are "G protein linked". G proteins are intracellular and when an extracellular neurotransmitter (the first messenger) binds to its receptor it changes the configuration of the intracellular part of the receptor and the G protein can then bind to the intracellular receptor site.
This triggers enzyme activation, which leads to the formation of another intracellular compound known (generically) as the second messenger.
Second messengers have a number of functions but the one of immediate relevance to antidepressant action is, that they trigger a chain of events that lead to the formation of proteins known as transcription factors. These are located in the cell nucleus and control gene expression and thus the capacity of the cell to produce a range of products from neurotrophic factors to receptor sites and uptake pumps.
The chain of events activated by the second messenger takes 7-14 days and accounts for the delay in onset of antidepressant action
Each step of this intra cellular sequence of events in response to antidepressant use takes a finite time to complete and the sum of these times plus the time for the neurotrophic factors to act accounts for the time delay between starting antidepressants and seeing evidence of symptomatic response.
The second mechanism by which the extracellular binding of neurotransmitters can influence intra-cellular events is by controlling the action of membrane ion channels. These ion channels regulate the flow of ions across the cell membrane and thus influence many aspects of neuron function including the sensitivity of the cell's receptor sites and its capacity to release neurotransmitter.
Our understanding of antidepressant action
This review has traced the development of our understanding of antidepressant action over the last 50 years. Imipramine was observed to have behaviour altering properties and this prompted the single neurotransmitter models, the permissive (dual transmitter) model, the synaptic cleft model (plus its Nobel Prize) and our current focus on intracellular events and regulation of gene activity.
Model development parallels understanding of patho-physiology and our understanding of depression has changed from that of a sometimes-recurrent illness with good inter-episode recovery towards that of an anatomical brain disease with microscopic and macroscopic atrophy with high levels of chronicity and often poor inter-episode recovery.
Antidepressant agents that were once thought to work by simply increasing neurotransmitters in synaptic clefts are now known to control multiple aspects of post-synaptic neuron function from sensitivity of receptors via ion channel activity, to the production of trophic factors and cellular components, such as receptor sites and uptake pumps, via the action of transcription factors on gene expression.
It is a gross oversimplification to believe that the actions of antidepressants are confined to the synaptic cleft and post-synaptic neuron. It should be noted that the mechanism of action within a living brain is much more complex due to anatomical inter-connections plus the presence of multiple other receptors and neurotransmitters that interact to regulate brain activity.
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2. Coppen A, Shaw DM, Malleson A, Eccleston E and Gundy G. Tryptamine metabolism in depression. British Journal of Psychiatry 1965; 111 (479); 993-998.
3. Prange A Jr,Wilson IC, Lynn CW, et al. L-tryptophan in mania. Contribution to a permissive hypothesis of affective disorders. Archives of General Psychiatry 1974; 30 (1); 56-62.
4. Leonard BE. Evidence for a biochemical lesion in depression. Journal of Clinical Psychiatry 2000; 61 (s6); 12-17.
5. Smith MA, Makino S, Altemus M, et al. Stress and antidepressants differentially regulate neurotrophin 3 mRNA expression in the locus coeruleus. PNAS USA 1995; 92 (19); 8788-8792. (Free full text article)
6. Nibuya M, Morinobu S and Duman RS. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. Journal of Neuroscience 1995; 15 (11); 7539-7547.
7. Duman RS, Heninger GR and Nestler EJ. A molecular and cellular theory of depression. Archives of General Psychiatry 1997; 54 (7); 607-608.
8. Kendler KS, Thornton LM and Gardner CO. Genetic risk, number of previous depressive
episodes, and stressful life events in predicting onset of major depression. American Journal of Psychiatry 2001; 158 (4); 582-586. (Free full text article)
9. Yildiz A, Gönül AS and Tamam L. Mechanism of actions of antidepressants: beyond the receptors. Bulletin of Clinical Psychopharmacology 2002; 12 (4); 194-200. (Free full text article)
Published on CNSforum 27 Apr 2005