The 1990s were the decade of serotonin. This was first isolated in the intestine in 1933 and called enteramine. It was rediscovered in blood vessels in 1947 and found to cause them to constrict, which led to it being called serotonin. In 1949, it was established that the chemical structure of serotonin was 5-hydroxytryptamine. Both names, 5-HT and serotonin, have remained in use. The name serotonin survives partly because SmithKline Beecham stumbled on the marketing appeal of the acronym SSRI (selective serotonin-reuptake inhibitor) for paroxetine.
Shortly before serotonin was discovered in the brain, lysergic acid diethylamide (LSD) had been discovered and it had been recognised that there were structural similarities between serotonin and LSD. This led, at the beginning of the psychopharmacological era, to great interest in the role that serotonin might play in mental illness. 23, 24 and 25 However, serotonin disappeared from view for over 20 years, partly because of the emergence in 1965 of the catecholamine hypothesis for depression.
By the early 1970s, it seemed that dopamine was the ‘psychosis’ neurotransmitter, noradrenaline (norepinephrine) the ‘mood’ neurotransmitter and acetylcholine the ‘dementia’ neurotransmitter (see Section 7). This left serotonin without an accompanying psychiatric disorder, and the one disorder left for it to be associated with was anxiety. While this parcelling out of disorders appears simplistic, there has always been some evidence to support it. We noted in 4 and 9 that the SSRIs appear to be in some way anxiolytic. Clomipramine, fluoxetine and fluvoxamine are useful for phobic and obsessional states as well as depression. This applies to all SSRIs and far less to antidepressants that do not inhibit serotonin reuptake.
With the development of the SSRIs, there was increasing interest in the serotonin system. This led during the 1980s to a sustained effort to characterise the receptors that serotonin acts on and to develop drugs specific to each of these.
SEROTONERGIC RECEPTORS AND DRUGS
Currently over 17 different types of serotonergic (S) receptor have been described. For our purposes, the ones of importance are the S1 and S2 receptors. Drugs acting on serotonergic receptors divide into agonists (drugs acting on a receptor) and antagonists (blocking the receptor) (Table 11.1). One of the key points to remember about the SSRIs is that they make more serotonin available at one or other of these receptors and they are therefore either indirect serotonergic agonists or antagonists.
| Agonist | Antagonist | |
|---|---|---|
| S1a | Buspirone | Spiperone |
| Flesinoxan | Propranolol | |
| Gepirone | ||
| Ipsapirone | ||
| S2a | d-LSD | Ketanserin |
| Mianserin | ||
| Mirtazapine | ||
| Trazodone | ||
| Nefazodone | ||
| All antipsychotics | ||
| S2b | mCPP | Ritanserin |
| S2c | Mianserin | |
| Mirtazapine | ||
| Agomelatonin |
SSRIs
The first point to note is that the SSRIs as a group are more clearly anxiolytic than antidepressant. When the SSRIs were launched the marketing imperatives dictated that these drugs were brought on the market as antidepressants rather than tranquillisers or anxiolytics. But it was clear that the companies would seek licences for anxiety states also and this they did during the 1990s. In recent years paroxetine, venlafaxine, sertraline and other SSRIs have been licensed for post-traumatic stress disorder (PTSD), obsessive–compulsive disorder (OCD), generalised anxiety disorder (GAD), social phobia and other anxiety states. What a licence means is not that clinicians are now able to prescribe these drugs for patients who are anxious but rather that companies have the chance to market anxiety, and they have been doing so to the tune of hundreds of millions of dollars per year, especially in the USA. This marketing has come complete with references to the chemical imbalance that is supposedly the cause of GAD or social phobia. What chemical imbalance? – lowered serotonin levels. There are also references to non-habit-forming paroxetine or to the fact that anxiety can be treated with benzodiazepines or SSRIs but the benzodiazepines cause dependence – with the clear implication that SSRIs do not cause dependence. There is in fact every reason to believe that SSRIs cause dependence just as frequently as benzodiazepines and that this dependence syndrome is in fact in many cases far more difficult to recover from than benzodiazepine dependence.
The side effects and interactions of the SSRIs are described in Chapter 5. These are the same for both anxiety and depression. Dependence on SSRIs is dealt with in Chapter 23.
S1 agonists
Buspirone, an S1
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