The tricyclic antidepressant imipramine and the monoamine oxidase inhibitor (MAOI) iproniazid were discovered in 1957 by Roland Kuhn and Nathan Kline respectively. ² What was discovered, however, was not just a drug but a disorder that the drug treated. There was no preconceived idea that these drugs should be antidepressant. Indeed, Kuhn thought he was testing out a new antipsychotic when he first gave imipramine to patients. Furthermore, there were a great number of stimulants available at the time, such as the amphetamines, but these did not appear particularly helpful for severe hospitalised depression. What Kuhn and Kline did, as much as find the compounds themselves, was to make visible a condition that responded to these compounds. It is this condition, variously called biological or major depression, which is in many respects the source of difficulties in specifying what the antidepressants do. We still do not know the nature of depression or its boundaries.

In 1965, the Medical Research Council (MRC) attempted to compare the MAOIs with the tricyclic antidepressants. When the MAOI phenelzine was compared with imipramine, electroconvulsive therapy (ECT) and placebo, imipramine and ECT came out as superior to both placebo and phenelzine, with phenelzine being no better than placebo. At the same time a serious hazard of the MAOIs, the cheese effect (see Ch. 5) had just been described. These joint findings put paid to the MAOIs, leaving the tricyclics as the dominant antidepressants for more than two decades, and it is from this group of drugs that the selective serotonin-reuptake inhibitors (SSRIs) came.

However, some clinicians had noted that drugs acting on the catecholamine system appeared to make people well by being energy-enhancing, whereas imipramine and clomipramine which also acted on the serotonin system, did something else. ³ This led Arvid Carlsson to make zimelidine in the 1970s, a drug that selectively blocked serotonin reuptake. Zimelidine had to be withdrawn because of side effects but it was succeeded by fluvoxamine, fluoxetine, sertraline, citalopram and paroxetine.

The term SSRI (selective serotonin-reuptake inhibitor) was coined by the marketers of paroxetine. Selective here means the drug does not act on the noradrenaline (norepinephrine) system – it does not mean ‘clean’ or ‘specific’. Paroxetine and other SSRIs have as many indiscriminate effects on different brain systems as the older drugs and none of the SSRIs is selective to the serotonin system. The term SSRI and the later SNRI (serotonin- and noradrenaline-reuptake inhibitors) are marketing rather than scientific or clinical terms.

What then do SSRIs do? Of the older drugs, clomipramine, which was the drug that had the greatest effects on the serotonin system, was also the drug that seemed to be in some way the most anxiolytic: it was found to be useful in phobic and obsessional states. 4 and 5 Since then the SSRIs have been licensed to treat social phobia, generalised anxiety disorder, panic disorder and obsessive–compulsive disorder, and more recently these drugs have been marketed very actively as anxiolytics. This suggests that blocking serotonin reuptake produces an essentially anxiolytic effect rather than anything else. If SSRIs are anxiolytics, this would explain why these drugs are relatively ineffective in cases of severe depression, which are much more likely to respond to older tricyclics or ECT.

The anxiolytic effects of SSRIs mean that antidepressants can have both climate and weather effects. The climate effect lies in breaking up a depressive syndrome, which takes anything from a few days to several weeks. The different kinds of antidepressant differ in their weather effects. Some can help break up a depressive syndrome by increasing energy levels (noradrenaline (norepinephrine) reuptake inhibitors) and others by producing an anxiolytic effect (SSRIs). Given that not all patients are equally suited to either of these effects, the art of treatment lies in matching patients to the most appropriate treatment for them.

It is also worth noting that most tricyclics and SSRIs were derived from antihistamines, and that many antihistamines have serotonin-reuptake inhibiting properties. These antihistamines can be anxiolytic in just the same way as SSRIs and can also cause the irritability, aggression and even suicidality that SSRIs can cause.

The tricyclic antidepressant trimipramine does not inhibit either noradrenaline (norepinephrine) or serotonin reuptake. It blocks noradrenergic and serotonergic receptors to produce tonic effects – increased sleep and appetite. It is very similar in effect to mirtazapine, mianserin, cyproheptadine and other drugs. It bears some similarities to trazodone and agomelatonin. This group provides an alternative to typical tricyclics and SSRIs.

Table 4.1 lists the major classes of antidepressant.

Until recently depression was divided into reactive and endogenous depressions. It was thought that ‘reactive’ depression, which comes on after a life event, was a milder, anxiety-based psychological problem that should not be treated with antidepressants. ‘Endogenous’ depression was supposedly a more severe biological illness, not reactive to life events, that was accordingly more appropriately treated with pills.

These ideas were shaped by the development of ECT and the tricyclic antidepressants. It appeared that the more severe depressions, and in particular those with clear physical features, responded convincingly to these physical treatments whereas the response of states of anxious misery or morbid distress was much less convincing. The endogenous depressions came to be seen as conditions that were presumed to arise by virtue of some biochemical change in the brain. The reactive or neurotic depressions were presumed to arise in response to life crises. ¹