European Journal of Clinical Pharmacology (2021) 77:931–932
https://doi.org/10.1007/s00228-020-02973-2
LETTER TO THE EDITOR
Add-on pharmacotherapy for patients
with first-episode schizophrenia: a clinical perspective
Qin Xiang Ng 1,2 & Joyce Wei Xin Chong 1 & Kuan Tsee Chee 1
Received: 30 May 2020 / Accepted: 27 July 2020 / Published online: 29 July 2020
# Springer-Verlag GmbH Germany, part of Springer Nature 2020
Dear Editor,
We read with great interest the study by Puranen and col-
leagues, which examined the use of antidepressants and mood
stabilizers in persons with first-episode schizophrenia (FES),
based on Finnish register data [1]. They found that among pa-
tients with FES, 35.4% initiated antidepressants and 14.1% ini-
tiated mood stabilizers (often in addition to the antipsychotic
olanzapine) within 3 years from the time of diagnosis.
However, it is unclear if there were clinical differences leading
to or arising from the prescription of these adjunctive medica-
tions. There was no information on the clinical indications or
severity of patient symptoms as well. Patients with FES have
significant clinical and biological heterogeneity [2], and they
are sometimes referred to as the “Group of Schizophrenias” [3].
Despite the introduction of newer antipsychotic medications,
the management of schizophrenia remains a substantial clinical
challenge. When faced with a patient that does not respond to or
cannot tolerate standard antipsychotic therapy, physicians have
limited treatment strategies. It does not help that a significant
proportion of patients with schizophrenia do not respond suffi-
ciently to antipsychotics and combination therapy is often re-
quired [4]. It is also apparent that individual patients may respond
better to certain combinations than another [5]. Puranen et al.
rightly pointed out that there is a paucity of studies and guidelines
pertaining to the use of antidepressants and mood stabilizers as
adjunct pharmacotherapy for patients with FES [1]. At present,
drug selection and augmentation strategies are typically based on
“trial and error” guided by the patient’s clinical response, rather
* Qin Xiang Ng
ng.qin.xiang@u.nus.edu
1
Institute of Mental Health, Buangkok Green Medical Park, 10
Buangkok View, Singapore 539747, Singapore
2
MOH Holdings Pte Ltd, 1 Maritime Square, Singapore 099253,
Singapore
than a more “scientific” paradigm. This should be the focus of
future studies.
In clinical practice, there are several other reasons why
patients with FES may require the addition of an antidepres-
sant, which is typically a selective serotonin reuptake inhibitor
(SSRI). Post-psychotic depression (that is, depressive symp-
toms in an individual emerging from a psychotic episode) is
also a well-recognized albeit poorly understood phenomenon
[6], and up to 50% of patients with schizophrenia have comor-
bid depression [7]. Adjunctive antidepressants may be bene-
ficial in these instances [8].
For patients with inadequate response in target schizophre-
nia symptoms, adding a second antipsychotic medication has
yielded largely negative results based on randomized trials
[9–11]. Based on our clinical experience, anecdotally, patients
with predominant auditory hallucination may respond better to
a trial of add-on of SSRI antidepressant. We are in the process
of collecting a case series of such patients. Several psychoana-
lytic theories posit that auditory hallucinations are internal cog-
nitive events and a response to intrusive experiences [12].
Much like intrusive thoughts, auditory hallucinations are often
distressing, ego-dystonic, and hard to control. It has also been
hypothesized that auditory hallucinations are internally gener-
ated speech perceptions localized in the left temporal lobe [13].
Some patients with schizophrenia who have insight attribute
auditory hallucinations to their own thinking, or “unconscious”
ruminations. This may partly explain the efficacy of SSRIs. A
ruminative self-focus is also linked to the development and
maintenance of depressive symptoms [14].
The recently published results of the DECIFER trial, a 52-
week, placebo-controlled add-on trial of citalopram, an SSRI
antidepressant, in patients with FES, reported significant im-
provements in negative symptoms with add-on citalopram
compared with placebo, especially among patients with a lon-
ger duration of untreated psychosis [15]. The study also found
that sexual dysfunction was more common in patients with
FES who received add-on citalopram but overall treatment-
emergent side effects and tolerability were comparable with
932
the placebo group [15]. It is thought that citalopram’s thera-
peutic benefit for negative symptoms is a primary effect rather
than secondary to its antidepressant actions.
Unfortunately, these remain postulated as a deep under-
standing of the biological (and therapeutic) mechanisms is still
sorely lacking.
Supporting data This manuscript has no associated data.
Author contributions Qin Xiang Ng conceived, designed, and carried out
the study, while Chee Kuan Tsee supervised the study. All authors con-
tributed to the writing and proofreading of the final manuscript. The final
manuscript was discussed and approved by all authors.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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