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Antidepressants versus other drugs

Last updated on May 26th, 2023

Comparisons between so-called antidepressant drugs and other sorts of drugs do not indicate that antidepressants have a specific effect on depression. Many other drugs show superior effects to placebo or equal effects to antidepressants in randomised trials, as shown in Table Randomised trials of other drugs for depression.

The fact that other substances had to compete with ideas about the specificity of antidepressants that were strongly entrenched by the mid-1960s makes these results even more remarkable. The case of benzodiazepines is instructive. In the 1960s, when these were still relatively new drugs, most studies found they were equal or superior to antidepressants

Table Randomised trials of other drugs for depression

Type of drug Results  
Neuroleptics Reserpine versusplacebo Review of 34



trials of


in depression

Reserpine superiorto placebo Neuroleptic

superior to

placebo in 10

out of 11


superior to

antidepressants in

3 comparisons,

equivalent in 14,

inferior in 2,


effects in

subgroups in 1

Barbiturates Amylobarbitone versusamitriptyline versus placebo No statistically significant difference between amitriptyline andamylobarbitone for 2 out of 3 depression ratings
Benzodiazepines Review of 20 studies of benzodiazepines compared with antidepressants 10 out of 20 studies found benzodiazepines were equal to antidepressants or superior to placebo
Alprazolam versus placebo and imipramine or amitriptyline Alprazolam superior to placebo and equal or superior to imipramine and amitriptyline
Stimulants Pemoline and methylphenidate (Ritalin) versus placebo Both stimulants superior to placebo
Imipramine versus Drinamyl (dexamphetamine plus amylobarbitone) Equal effects
Buspirone Five studies of buspirone versus placebo in major depression with anxiety Buspirone superior overall and for core symptoms of depression as well as anxiety
Buspirone versus placebo for major depression Trend towards superiority of buspirone
Opiates Buprenorphine versus placebo Buprenorphine superior
Atropine Review and meta-analysis of nine trials comparing antidepressants with an active placebo containing atropine One study found a significant effect of antidepressant; others found small and non significant differences
St John’s wort St John’s wort (hypericum) versus placebo, imipramine and paroxetine St John’s wort superior to placeboand equivalent to antidepressants

for people with depression. By the 1970s, most studies found the antidepressant was superior. Despite finding that half of the studies they reviewed showed equal or superior effects with benzodiazepines, by 1978 reviewers Schatzberg and Cole concluded confidently that benzodiazepines ‘are less effective than standard antidepressants in the treatment of several types of depressive illnesses’. But when a new benzodiazepine, alprazolam, was produced and marketed in the 1980s, studies reported that it was effective in treating depression, and not just depression with anxiety.

Almost all studies comparing antidepressants with neuroleptic drugs found that neuroleptics were equivalent or better. Two of these studies reported that the antidepressant was superior for patients with “retarded” depression, whereas the neuroleptic was superior for anxious or neurotic patients. This is readily understandable, given what we know of the drug-induced effects of neuroleptics. Their deactivation effects are likely to compound psychomotor retardation and reduce agitation and anxiety. Reserpine, the drug that was believed to induce a depressive state, was found to be clearly superior to placebo for the treatment of depression in an early trial conducted at the Maudsley hospital in London.

Antidepressants versus other drugs

Despite early convictions that stimulants were ineffective for depression, a large and well-conducted trial by Rickels et al. (1970), involving 120 patients, demonstrated clear superiority of two stimulants over placebo in a four-week trial.

In the early days of antidepressant research, some investigators worried about the possibility of unblinding. In order to reduce this problem they used a placebo containing an active substance to mimic some of the side effects of the antidepressant drugs, instead of the physiologically inert substances that placebos are usually made of such as chalk and lactose. Atropine was the substance used because it produces the same anticholinergic effects that the tricyclic antidepressants produce, such as a dry mouth, constipation and blurred vision, but is not thought to have any specific antidepressant action.

However atropine is mildly stimulant, and easily distinguishable from the effects of tricyclic antidepressants, which are strongly sedative, so it is likely that even these studies were not truly double blind. One of the studies used a small amount of a barbiturate as well to produce a mild sedative effect. All but one of these studies found that the differences between the antidepressant and the active placebo were small and not statistically significant. All the inpatient studies found no difference between the active placebo and the antidepressant, and all but one of the outpatient studies found only small differences. The quality of these studies has rightly been criticised and it has been pointed out that most found differences in favour of the antidepressants.

However there is evidence that the use of an active placebo was insufficient to disguise the nature of the treatment. For example, one trial reported that side effects were substantially greater with the antidepressants used compared with the active placebo. Two trials that asked raters to guess what medication people were taking showed they could guess better than chance. In one of these trials there was an association between guessing that patients were taking antidepressants and higher improvement ratings, suggesting that ratings may have been influenced by expectations of treatment.

In contrast a large trial of a naturally occurring biological compound called Substance P found no detectable difference from placebo. However the fact that substance P was associated with almost no side effects means that it was probably not distinguishable from an inert placebo. Paroxetine was used as the active comparator in these trials and the published paper suggests that its antidepressant effects were ‘confirmed’. In fact the difference between paroxetine and placebo was a miniscule 2-3 points on the Hamilton Rating Scale for Depression.

Drugs that are classed as antidepressants have a wide variety of pharmacological actions themselves. A recent meta-analysis showed that there was no distinction between drugs with different types of actions; that they all seemed to have a similar magnitude of effect. This suggests that the superiority that antidepressants and other drugs sometimes show over placebo is not related to a specific pharmacological action. Therefore, it seems likely that it is due to a combination of non-specific pharmacological and psychological factors.

The pharmacological factors are the drug-induced effects such as sedation, which may produce temporary relief of some symptoms or features of depression. Alternatively, sedation or the indifference associated with neuroleptics might simply mask or blunt people’s emotions. The psychological factors are the positive expectations that are associated with knowing that one is taking an active compound; in other words, the amplified placebo effect.

When confronted with this evidence, mainstream psychiatric commentators have either chosen to ignore it, or they have suggested that drugs that are not conventionally recognised as antidepressants may possess ‘antidepressant properties’. The trouble with this argument is that if everything that produces some effect in depression is immediately assumed to be an ‘antidepressant’, with the implication that it has a disease-specific action, then there is no way of distinguishing a specific from a non-specific effect.

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