The best tricyclic antidepressants remain important and effective treatments for major depressive disorder. However the relatively higher toxicity of some of them in overdose (especially dothiepin-- see ‘toxicity’), and other side effects, persuade some authorities say that it is inappropriate, and a few even say negligent, to use them for first line treatment in primary care.

Such views may cause some to make a selective serotonin reuptake inhibitor their usual first choice unless there is a special medical reason not to - and there are quite a few of those.

In my opinion the evidence on toxicity does not logically support this widely advocated but simplistic interpretation and approach. For instance: some of the new drugs are definitely more toxic than some of the older drugs, and the evidence that some old drugs are more effective than most of the new drugs remains strong-- especially for amitriptyline and clomipramine and tranylcypromine. (see other notes). Also remember that some 95% of deaths by suicide are not caused by the antidepressant drug prescribed.

For major ('endogenous') depressive illness (in primary care) there are various lines of evidence and logic indicating sertraline is a logical first choice, especially in less severe cases and where first line treatment with a tricyclic antidepressant is not appropriate (see note 538). This is because sertraline has a particularly favourable pharmacokinetic and side effect profile with a lesser propensity for interactions. Three of the other selective serotonin reuptake inhibitors have significant and sometimes dangerous interactions, mostly via cytochrome P450 enzymes; these are fluoxetine (2D6 and 3A4), paroxetine (2D6) and fluvoxamine (1A2 and 2C9 /19). For this reason it is hard to justify their routine use by primary care doctors who are likely to encounter difficulties keeping up with the multiple possible interactions.

I advise it is prudent and logical not to routinely use fluoxetine, paroxetine or fluvoxamine as first line treatment in primary care settings because some of these interactions may precipitate serious morbidity.

For more severe illnesses my analysis of the literature, combined with experience, leads me to have doubts about the relative effectiveness of selective serotonin reuptake inhibitors, especially when compared to clomipramine. They work but it is a question of degree. The evidence is that the more severe the illness the less well SSRIs (and some other newer drugs) work.

The majority of controlled trials indicate selective serotonin reuptake inhibitors induce full remission of illness in only a small proportion of the cases treated (note response rates usually quoted for drugs trials may seem good, but they relate to a 50% decrease in rating scale scores, which is a much less stringent criterion for success than wellness or full remission).

Thus the evidence indicates that SSRIs are often an inadequate treatment for more severe depressive illness.

I advise great caution if treating "endogenous" depression with these drugs, you will often encounter degrees of improvement that fall well short of full remission of illness. That is unacceptable, because full remission of illness is the achievable goal for most patients.

Serotonin and noradrenalin reuptake inhibitors (SNRIs): Venlafaxine may be an SNRI, it may be particularly effective especially for more severe illnesses. However, the evidence to support that notion remains incomplete, some recent findings indicate venlafaxine may less effective than amitriptyline.

The experience supporting the superior effectiveness of serotonin and noradrenalin reuptake inhibitors (SNRIs) is substantive for clomipramine. Clomipramine may be well worth trying before venlafaxine. My experience of switching patients from clomipramine to venlafaxine is that many have a less satisfactory response on venlafaxine; conversely, many who fail with venlafaxine do well with clomipramine.

Despite the absence of muscarinic blocking and other TCA-like effects (in vitro) venlafaxine has more side effects in practice than might have been expected ‘on paper’.

Its ability to block NA reuptake is weak at normal doses, so it may be functioning more as an “SSRI”. The precise mode of action of venlafaxine, and its usefulness, relative to other drugs or combinations, is still not clearly evident.