DOI: 10.25934/pr00007104
title: Item-level effects of adjuvant olanzapine and/or olanzapine monotherapy in treatment-resistant depression

description: Depression is a debilitating and sometimes lethal condition. Modern antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs) have been shown to be safe and reasonably effective in treating the condition, but roughly 1/4-1/3 of all patients with depression respond poorly or not at all. There exist a number of strategies to help these people, with one of the more common being the addition of a so-called 'atypical antipsychotic', i.e. a newer antipsychotic that, among other things, also influence the serotonin system. This study proposes to investigate the effects of add-on treatment with olanzapine, the first of these drugs to be approved as an adjunctive treatment in patients with depression that have responded inadequately to an SSRI alone. 

The mode of action of SSRIs is poorly known. Upon administration, they rapidly block the serotonin transporter, increasing the amount of serotonin available in synapses. This is however unlikely to be directly related to their therapeutic effects. On the basis of clinical observations (such as that it is common that anxiety increases during the first few days of SSRI treatment), human brain imaging studies and data from animal studies, at least the anxiety disorders would seem to be states characterised by an overactive serotonin system, something that is counteracted by long- but not short-term SSRI administration. There exist a number of theories attempting to explain exactly how SSRIs work in treating depression and anxiety beyond the effects in the synapses during the first few days; modulation of neuroplasticity (i.e., the ability of neurons to form new and modulate/remove old connections), stabilising serotonergic neurotransmission and effects on inflammation in the central nervous system are some examples, but no real consensus exists. 

Though mostly used to treat psychotic disorders such as schizophrenia as well as bipolar mania, atypical antipsychotics have, partly due to their effects on the serotonin system, been investigated as treatment for a number of other psychiatric disorders. In the case of depression, they have been found to be able to rapidly induce an antidepressant effect in patients responding poorly to an SSRI alone. The doses employed are usually markedly lower than when the drugs are used in the treatment of psychosis or mania, but they may still have considerable side-effects and there are outstanding questions regarding their efficacy, especially when looking at effects on the core symptoms of depression, as well as how they compare to each other.

Most studies of psychiatric disorders employ rating scales where a number (usually more than a dozen) symptoms are rated and a total sum score computed. This is then what is compared when e.g. a new drug or a new psychotherapeutic method is tested in a clinical study - however, the specific symptoms (often called 'items') are seldom or never reported in clinical studies. This limits the usefulness of traditional meta-analyses as, these then need to be based on a sum reflecting the effects on a number of symptoms. This obscures much information, as the drug might have affected a certain symptom both positively, negatively (that is; it might have caused side-effects relating to, i.e., sleep), or have had no effect at all. Thus, a very effective antidepressant that also causes a lot of side-effects would register as not particularly effective at all while a drug that is mostly a sedative and a tranquiliser would register as being effective, even though the specific antidepressant effect might be mild or not there at all. Newer rating scales have been designed to avoid picking up too much of likely side-effects, but for the main rating scale employed in almost all antidepressant trials since the 70-ies, the Hamilton Depression Rating Scale (HDRS), this is a major problem.

We have previously conducted extensive research regarding item-level effects in SSRIs, and have been able to demonstrate that vital information regarding the effectiveness, safety and tolerability of antidepressant drugs may be missed when conclusions are drawn on the basis of general effects on a rating scale and where no individual data is available. This proposal is part of larger project investigating the usefulness of dopamine modulating drugs in treating depression including, apart from meta-analyses and animal studies, also a clinical trial of the dopamine and serotonin modulator OSU-6162 as add-on treatment in SSRI-resistant depression. Here we wish to investigate the first of the atypical antipsychotics to receive FDA approval as add-on treatment in treatment-resistant depression; olanzapine. We will compare effects both within and between treatment groups (SSRI+olanzapine, SSRI+placebo and placebo+olanzapine). Our analyses will focus how 'specific' the antidepressant effect of the combination treatment, how much of a positive effect that is related to a positive influence on sleep, effects on anxiety and suicidality, as well as how sex and age might influence treatment response. We expect to later expand these analyses to the other atypical antipsychotics used as add-on treatment for depression, in other to be able to do comparative analyses.