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Page Background European Psychiatry 41S (2017) S3–S5

Available online at


25th European Congress of Psychiatry

Joint Symposia

Joint symposium: How long do we have to wait for

the antidepressant effect?


Joint symposium: How long do we

have to wait for the antidepressant

effect? Mechanisms of action for delay

of onset response to antidepressants

F. Artigas

Institut d’investigacions biomèdiques de Barcelona, Spain

Major depressive disorder (MDD) is a severe psychiatric syndrome

with very high prevalence and socioeconomic impact. Monoamine-

based antidepressant drugs (AD) display slow onset of action and

limited efficacy. Preclinical studies show that ADs trigger a series

of slow adaptive mechanisms that limit the clinical response.

These mechanisms result from the pharmacological blockade of

monoamine transporters (SERT, NET) and involve presynaptic,

such as autoreceptor desensitization (e.g., 5-HT


and 5-HT



serotonin neurons) as well as postsynaptic mechanisms, such as

increased neurogenesis and expression of trophic factors, increased

dendritic complexity, etc.

Given the strong homeostasis of serotonin and noradrenaline

neurons, a way to improve antidepressant action is to prevent

self-inhibitory presynaptic mechanisms mediated by auto- and

heteroreceptors after reuptake blockade. This strategy was used

in the past with the non-selective 5-HT


antagonist pindolol and

has been incorporated by two recently developed AD (vilazodone

and vortioxetine). Likewise, new molecular strategies using RNA

interference (RNAi) show that the modulation of gene expression

in serotonin neurons offers a great potential. Hence, local or intr-

nasal administration of small interfering RNA (siRNA) molecules

targeting SERT or 5-HT


autoreceptors evokes rapid and robust

antidepressant-like effects in rodents.

Moreover, glutamatergic drugs such as the non-competitive

NMDA receptor antagonist ketmaine, offer a potential for the

development of fast-acting AD due to its rapid and persistent

antidepressant effects in treatment-resistant unipolar and bipo-

lar patients after single i.v. infusion, an effect that likely involves

the activation of AMPA receptors in ventral areas of the cin-

gulate gyrus and the subsequent fast activation of serotonergic


Disclosure of interest

F.A. has received consulting honoraria

on antidepressant drugs from Lundbeck and he has been PI

of grants from Lundbeck. He is also co-author of the patent

WO/2011/131693 for the siRNA and ASO (antisense oligonu-

cleotides) molecules.


What do clinical trials tell us about

antidepressant delayed onset of


J. Rabinowitz

Bar Ilan University, Israel

Response to antidepressants in major depressive disorder is highly

variable and determinants are not well understood. Presentation

will provide clinical trial data on time to response and deter-

minants of response to antidepressant treatment. Data is from

the Innovative Medicines Initiative funded NEWMEDS collabo-

ration, a large public-private collaboration which assembled the

largest dataset of individual patient level information from ran-

domized placebo-controlled trials of antidepressant drugs. Studies

were conducted by four large pharmaceutical companies. Dataset

includes placebo-controlled trials of citalopram, duloxetine, esc-

italopram, quetiapine and sertraline in adults with MDD. We

examined patient and trial-design-related determinants of out-

come as measured by change on Hamilton Depression Scale

or Montgomery–Asberg Depression Rating Scale in 34 placebo-

controlled trials (drug,


= 8260; placebo,


= 3957). While it is

conventional for trials to be 6–8 weeks long, data presented will

show that drug-placebo differences were observable at week 4

with nearly the same sensitivity and lower dropout rates. Having

any of these attributes was significantly associated with greater

drug vs. placebo differences on symptom improvement: female,

patients being middle aged, increasing proportion of patients on

placebo, excluding all patients from centers with high placebo

response regardless of active treatment response, using active run

in periods and including self-report measures. Proof of concept tri-

als can be shorter and efficiency improved by selecting enriched

populations based on clinical and demographic variables, ensur-

ing adequate balance of placebo patients, and carefully selecting

and monitoring centers. In addition to improving drug discovery,

patient exposure to placebo and experimental treatments can be


Disclosure of interest

I have received research grant(s) support

and/or travel support and/or speaker fees and/or consultant fees

from Takeda, Minerva, Intra-cellular Therapies, Janssen (J&J), Eli