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\begin{document}

\title{Potential cytochrome P450--mediated drug-drug interactions with
selective serotonin reuptake inhibitors: A retrospective analysis of a
university hospital prescription database}



\author[1]{Gul Ozbey}%
\author[1]{Mehmet Yardımsever}%
\author[1]{Pelin Rezzan ÖZ}%
\author[1]{Hazal TAŞ}%
\affil[1]{Akdeniz University Medical Faculty}%


\vspace{-1em}



  
  \date{June 07, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
Rationale, aims and objectives The study aimed to investigate the rate
of the potential cytochrome P450 (CYP450)-mediated drug-drug
interactions (DDIs) between selective serotonin reuptake inhibitors
(SSRI) and other drugs, and identify the most common CYP450-interacted
SSRI-drug combinations in real-life clinical practice. Methods This is a
retrospective analysis of SSRI prescribing data from the Akdeniz
University Hospital database, a tertiary hospital database in Turkey.
Prescriptions which were included an SSRI had been selected (from
January 2014 to December 2018). Lexicomp\selectlanguage{ngerman}® Online\selectlanguage{english} was used to identify
potential CYP450-mediated DDIs. Results A total of 7.5\% of SSRI
prescriptions were at risk of potential CYP450-mediated DDIs; 74.4\% (n
= 67) of the pDDIs were identified as category D modification of
treatment should be considered. Antipsychotics were involved in 71.8\%
category D potential DDIs and 83.6\% category C potential DDIs. The
medications most frequently identified in combination with SSRIs were
risperidone (31.7\%) and aripiprazole (31.6\%). Finally, CYP2D6 and
CYP3A4 were the two most commonly affected CYP450 isozymes. Conclusions
Prescribing antipsychotic-SSRI pairs interacting via CYP450 may increase
serum concentrations of antipsychotics. Using DDI alert software while
writing electronic prescriptions during clinical practice may reduce the
frequency of ADRs.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Title :}

Potential cytochrome P450--mediated drug-drug interactions with
selective serotonin reuptake inhibitors: A retrospective analysis of a
university hospital prescription database

\textbf{Running title:}

CYP450 interactions in SSRI prescriptions

\textbf{Authors :} Ozbey G\textsuperscript{1}, Yard\selectlanguage{polish}ı\selectlanguage{english}msever
M\textsuperscript{2}, Oz PR\textsuperscript{1}, Tas H\textsuperscript{2}

\textbf{Adresses of authors:}

1. Gul Ozbey, Akdeniz University Medical Faculty, Department of
Pharmacology, Dumlupinar Street, 07070, Antalya, Turkey,
gulozbey@gmail.com, ORCID No: 0000-0002-3616-0052

2. Mehmet Yard\selectlanguage{polish}ı\selectlanguage{english}msever, Akdeniz University Medical Faculty, Department of
Biostatistics, Dumlupinar Street, 07070, Antalya, Turkey,
mehmet@akdeniz.edu.tr, ORCID No: 0000-0003-0838-0303

3. Pelin Rezzan Oz, Akdeniz University Medical Faculty, Department of
Pharmacology, Dumlupinar Street, 07070, Antalya, Turkey,
ecz.pelinoz@gmail.com, ORCID No: 0000-0002-3081-8167

4. Hazal Tas, Akdeniz University Medical Faculty, Department of
Biostatistics, Dumlupinar Street, 07070, Antalya, Turkey,
h\_tas90@hotmail.com, ORCID No: 0000-0002-0872-7998

\textbf{Corresponding Author:}

Gul OZBEY, MD, Associated Professor, Akdeniz University, Medical
Faculty, Department of Pharmacology, 07070, Antalya, Turkey, Phone
number: +90 242 2496925, Fax number: +90 242 2274482, e-mail:
gulozbey@gmail.com

\textbf{Abstract}

Rationale, aims and objectives

The study aimed to investigate the rate of the potential cytochrome P450
(CYP450)-mediated drug-drug interactions (DDIs) between selective
serotonin reuptake inhibitors (SSRI) and other drugs, and identify the
most common CYP450-interacted SSRI-drug combinations in real-life
clinical practice.

Methods

This is a retrospective analysis of SSRI prescribing data from the
Akdeniz University Hospital database, a tertiary hospital database in
Turkey. Prescriptions which were included an SSRI had been selected
(from January 2014 to December 2018). Lexicomp\selectlanguage{ngerman}® Online\selectlanguage{english} was used to
identify potential CYP450-mediated DDIs.

Results

A total of 7.5\% of SSRI prescriptions were at risk of potential
CYP450-mediated DDIs; 74.4\% (n = 67) of the pDDIs were identified as
category D modification of treatment should be considered.
Antipsychotics were involved in 71.8\% category D potential DDIs and
83.6\% category C potential DDIs. The medications most frequently
identified in combination with SSRIs were risperidone (31.7\%) and
aripiprazole (31.6\%). Finally, CYP2D6 and CYP3A4 were the two most
commonly affected CYP450 isozymes.

Conclusions

Prescribing antipsychotic-SSRI pairs interacting via CYP450 may increase
serum concentrations of antipsychotics. Using DDI alert software while
writing electronic prescriptions during clinical practice may reduce the
frequency of ADRs.

\textbf{Keywords}

drug interactions; selective serotonin reuptake inhibitors; cytochrome
P450; prescription

\textbf{Introduction}

Antidepressants are one of the most widely prescribed drugs with an
increasing trend in use during the past decades \textsuperscript{1}.
Besides the introduction of selective serotonin reuptake inhibitors
(SSRIs), the rise in use has also been explained by the prolongation of
treatment duration of antidepressants \textsuperscript{2}. In addition
to major depression, SSRIs are also indicated for a wide range of
psychiatric disorders, including obsessive-compulsive disorder,
posttraumatic stress disorder, panic disorder, generalized anxiety
disorder, and eating disorders \textsuperscript{3}. Long-term use of
antidepressants puts the treatment at increasing risk of
co-administration with other drugs in time, which can result in toxicity
or reduced efficacy via drug-drug interactions
(DDIs)\textsuperscript{2}.

DDIs are common preventable causes of adverse drug reactions (ADR),
which can occur at the pharmacodynamic or pharmacokinetic
level\textsuperscript{4}. Since cytochrome P450 (CYP450) isoenzymes
responsible for the metabolism of many antidepressants, CYP450-mediated
pharmacokinetic DDIs are frequently seen among antidepressant
users\textsuperscript{5}. Several antidepressants can markedly inhibit
different CYP450 enzyme activities or could be a substrate for
them\textsuperscript{5}. Compared with the other antidepressant groups,
SSRIs usually inhibit one or more CYP450 isozyme moderately to
substantially at their therapeutic doses \textsuperscript{6}. Also, it
has been known that the large inter-individual variability observed in
serum concentrations of SSRIs results mainly from variation in the
activities of CYP450 enzymes \textsuperscript{7}. Besides, SSRIs display
differences in their potential for CYP-mediated DDIs due to the
inhibition capacities on CYP450 enzymes \textsuperscript{8}. Therefore,
avoiding co-administration CYP450 interacting drugs with SSRIs could
reduce ADRs via preventing CYP450-mediated DDIs.

In the literature, little is known about the frequency and severity of
CYP450-mediated DDIs among SSRIs users. Almost all prior studies have
examined all the DDIs in broad psychiatric populations. In this study,
we focused on potential CYP450-mediated DDIs in prescriptions of SSRIs.
Therefore, we aimed to examine the reciprocal potential CYP450-mediated
DDIs between the SSRIs and other drugs in terms of frequency and
severity.

\textbf{Methods}

Study design

This was a retrospective cross-sectional study performed at a tertiary
hospital in Turkey. The study was approved by the Akdeniz University
Clinical Research Ethics Committee (2019-421-05).

Procedures

All SSRI prescriptions stored electronically in the Akdeniz University
Hospital database between January 2014 and December 2018 were assessed.
Data evaluated for CYP450-mediated DDIs potential according to the
Lexi-Interact Online database. DDIs are categorized into five groups
depending on their severity of clinical significance. The
recommendations of the database for per category of DDIs as (A) No known
interaction; (B) No action needed; (C) Monitor therapy; (D) Consider
therapy modification; (X) Avoid combination. Potential CYP-mediated
drug-drug interactions were classified as category X, D, and C, using
according to Lexicomp(r) Online\selectlanguage{english}.

Statistical Analysis

All data were analyzed using descriptive statistics. Data were expressed
as frequency and percentage.

\textbf{Results}

Potential CYP450-mediated DDIs rates in SSRI prescriptions

A total of 7.5\% (n=3.318) of all SSRI prescriptions (n=44.081) were
associated with CYP450-mediated DDIs potential. Based on the
Lexi-Interact Online database, about 74.4\% of interactions belonged to
category D, 25.4\% were at category C and 0.2\% were at category X
(Table 1). In all SSRI prescriptions, the rate of D and C type DDIs was
5.6\% and 1.9\%, respectively (Table 1).

The majority of potential CYP450-mediated interactions were identified
in fluoxetine (50.9\%), paroxetine (26.4\%), and sertraline (13.4\%)
prescriptions, whereas the rest were identified in escitalopram (4.5\%),
fluvoxamine (3.7\%), citalopram (1.1\%) prescriptions (Table 2). D type
interactions were frequently prescribed with fluoxetine (62.8\%) and
paroxetine (29.6\%). However, most C type interactions involved in
sertraline prescriptions (52.6\%) (Table 3).

We next investigated the ratios of CYP450-mediated interaction
potentials for each SSRI, separately. Among all SSRIs, fluvoxamine
(21.6\%), paroxetine (18.3\%) and, fluoxetine (17.8\%) prescriptions
were with the high risk for the potential of CYP450-mediated DDIs,
whereas prescriptions including escitalopram (1.1\%), sertraline
(3.0\%), and citalopram (4.4\%) were at low risk of the potential (Table
2). In terms of DDIs category, fluoxetine (16.4\%) and paroxetine
(15.3\%) prescriptions were at high risk for D type interaction and,
prescriptions of fluvoxamine (12.9\%) were at the highest risk of
potential for C type interaction. Prescriptions that involved category X
(n=7) belonged to fluvoxamine and fluoxetine; 6 of them fluvoxamine and,
only 1 of them fluoxetine.

Most frequent potentially CYP450-mediated interacted drugs with SSRIs

The most common potentially interact drug group was antipsychotics
(n=2481, 74.8\%) followed by other antidepressants (n=325, 9.8\%),
beta-blockers (n=325, 6.9\%) and, antiepileptics (n=135, 4.1\%) (Figure
1). Antipsychotics were associated with 71.8\% (n=1775) of all category
D interactions and 83.6\% (n=706) of C category interactions. Among
antipsychotics, the two most frequent interact drugs were risperidone
(n=1051, 42.4\%) and aripiprazol (n=1047, 42.2\%).

Table 4 presents the drug pairs that most frequently involved category
D\&C interactions. Fluoxetine-risperidone combination was the most
common interactions in category D, accounting for 31.1\% of all D type
interactions, the rest were fluoxetine combined with aripiprazole
(16.8\%), paroxetine combined with risperidone (11.4\%), paroxetine
combined with aripiprazole (5.9\%) and, paroxetine combined with
mirtazapine (4.6\%). Among the most common drug pairs in category C, the
most five dispensed combinations were sertraline combined with
aripiprazole (46.9\%), paroxetine combined with clozapine (14.1\%),
fluoxetine combined with clozapine (12.1\%), fluvoxamine combined with
aripiprazole (9.1\%) and, sertraline combined with carbamazepine
(5.6\%).

Most frequent affected CYP450 enzymes from pDDIs in SSRIs prescriptions

In the present study, a total of 37 different drugs potentially
interacted with SSRIs via at least one CYP450 enzymes (Supplementary
data). Besides, CYP450-interact 64 different drug pairs were determined
in pDDIs prescriptions (Supplemental data). The most interact CYP450
isoenzyme was CYP2D6 (n=2958) followed by CYP3A4 (n=305), CYP2C9/19
(n=51) and, CYP1A2 (n=44) (Table 5). The majority of CYP2D6-mediated
pDDIs were determined in fluoxetine prescriptions (n=1674, 56.6\%).
Escitalopram was associated with 49.2\% (n=150) of all CYP3A4-mediated
pDDIs. All of the CYP1A2-mediated pDDIs were identified in fluvoxamine
prescriptions (n=44). Similarly, all of the CYP2C9/19-mediated pDDIs
were identified in fluoxetine prescriptions (n=51).

\textbf{Discussion}

SSRIs, a commonly prescribed antidepressant group, could produce
clinically significant inhibition of one or more CYP450
isozymes\textsuperscript{9}. Nevertheless, polypharmacy with SSRIs is
recommended for several psychiatric disorders by clinical
guidelines\textsuperscript{10}, the insufficient evidence on treatment
modifications related to DDIs as a consequence of
polypharmacy\textsuperscript{11}. While pharmacokinetic DDIs are often
predictable, knowledge of the rate, level, clinical magnitude of
CYP-mediated DDIs between SSRIs and other drugs is essential. Thus, it
is important to know of CYP-mediated DDIs in SSRI prescriptions in terms
of most prescribed SSRI, drugs that interacted with SSRIs, and common
drug pairs.

Earlier studies have examined CYP450-mediated pDDIs in SSRI
prescriptions specifically, covered only fluoxetine, paroxetine, and
sertraline, have shown higher rates for
interactions\textsuperscript{12,13}. In the first study mentioned
earlier, the concomitant use of CYP2D6/3A4 metabolized medications in
patients who were also receiving fluoxetine, paroxetine or sertraline
were detected as 25.5\% \textsuperscript{12}. The second study, by
Preskorn et al., found 11\% of the potential to cause CYP-mediated DDIs
in patients taking fluoxetine, paroxetine, or sertraline
\textsuperscript{13}. In the present study, we have shown the rate of
CYP450-mediated pDDIs for all CYP450 isoenzymes in fluoxetine,
paroxetine, sertraline, fluvoxamine, citalopram, and escitalopram
prescriptions as 7.5\% in a tertiary hospital.

It is important to point out that in this study Category D interactions
constituted 74.4\% of all CYP-mediated interactions. Also,
antipsychotics are the most commonly identified CYP-mediated interacted
drug group in D category (71.8\%). Among the antipsychotics, risperidone
(42.4\%) and aripiprazole (42.2\%) were the two most frequently
interacted drugs. Thus, modification of drug therapy is needed when
using SSRIs and risperidone/aripiprazole concomitantly.

Our results have shown that approximately half of the potential
CYP450-mediated interactions were prescribed with fluoxetine (50.9\%).
For nearly 40 years, different formulations of fluoxetine as a strong
inhibitor of CYP2D6 and CYP2C9 have been prescribed for many psychiatric
disorders \textsuperscript{14}. Also, a majority of pDDIs (91.9\%)
determined in fluoxetine SSRI prescriptions fell into category D, which
most frequently combined with risperidone and aripiprazole.
Co-administration of fluoxetine with risperidone or aripiprazole can
cause significant elevations in the serum levels of risperidone and
aripiprazole metabolized via CYP2D6 \textsuperscript{15,16,17}. When
considering prescribing fluoxetine to patients currently taking
risperidone/aripiprazole or vice versa, it is reasonable to reduce
risperidone/aripiprazole doses\textsuperscript{11}.

Our findings are consistent with previous research concerning the most
common interacted CYP enzymes were CYP2D6 and CYP3A4 in SSRI
prescriptions. In a study, Gregor et al. reported that 25.5\% of
patients treated with fluoxetine, paroxetine, and sertraline experienced
concomitant use with at least one CYP2D6 or 3A4 metabolized
drug\textsuperscript{12}. Similarly, Preskorn et al. observed that of
all patients receiving fluoxetine and/or paroxetine, 8\% were also
receiving a potential CYP2D6-interacted drug with a narrow therapeutic
index\textsuperscript{13}. Furthermore, a study which investigated
CYP-mediated pDDIs in all psychiatric population has shown that CYP2D6
and CYP3A4 are the most affected CYP isoforms \textsuperscript{18}.
These results are explainable by the fact that SSRIs inhibit
predominantly CYP2D6 isoform and CYP2D6/3A4 isoforms metabolize a major
part of SSRIs.

Our analysis concluded that there are also other safer SSRI-drug pairs
not interacted at least via other CYP isoenzymes (Table 6). In this
study, risperidone or aripiprazole was frequently combined with
fluoxetine or paroxetine (Table 4). But, these combinations may lead to
an increase in serum concentrations of risperidone and aripiprazole via
inhibition of CYP2D6 \textsuperscript{15,19,20,21}. If therapeutic
efficiency is sufficient in combination with risperidone or
aripiprazole, it seems to add on SER, ESC, FLV, CIT instead of
fluoxetine or paroxetine is safer \textsuperscript{22,23,24,25}. Add on
olanzapine to fluoxetine or paroxetine treatment is another choice for a
safer drug combination in terms of CYP-mediated drug
interactions\textsuperscript{26}.

There are some limitations of the current study. First, the study was
limited to analyzing prescriptions dispensed in a university hospital,
and therefore, the results may not reflect all clinical practice.
Second, we evaluated only CYP-mediated DDIs specifically,
pharmacodynamic interactions or other types of pharmacokinetic DDIs were
not included. Therefore, we cannot recommend another drug pair instead
of interacting combinations in this study. Furthermore, we used only
Lexi-comp to identification DDIs. Thus, it is likely that these findings
may differ if we use another source for drug interactions. Additionally,
our data contained the drugs solely in the same prescriptions, not all
medications the patient used. Thus, it was not possible to find the rate
of DDIs for each patient. Because the e-prescriptions only included
information about the medication prescribed, the daily dose of drugs
could not be evaluated in terms of DDIs potential.

In summary, as the CYP isoenzymes playing a major role in the metabolism
of SSRIs, avoiding the use of SSRI\&CYP-interacted drug combinations is
a rational strategy for diminishing CYP-mediated pDDIs during the SSRIs
therapy. Since most of the CYP-mediated pDDIs fell into category D, it
seems that concomitant prescription of SSRIs and risky drugs could
result in ADRs. Our results may help physicians to identify and avoid
the frequent CYP-interacted SSRI-drug combinations in a real-life
setting. Further studies are needed to assess the rate of pDDIs for all
medications a patient uses.

\textbf{Key points}

\begin{itemize}
\tightlist
\item
  7.5\% of SSRI prescriptions were associated with CYP450 mediated DDI
  potential
\item
  Majority of prescriptions with CYP450-mediated pDDIs were fell into
  category D
\item
  Approximately half of prescriptions with CYP450 mediated pDDIs were
  fluoxetine prescriptions
\item
  Antipsychotics were associated with approximately three-quarters of
  CYP450-mediated pDDIs
\end{itemize}

\textbf{Declaration of Interest}

The authors declare that they have no conflicts of interest.

\textbf{Funding}

None.

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\textbf{Appendices}

Table 1. Potential CYP-mediated DDIs in the SSRI prescriptions

Table 2. The frequencies and percentages of potentially CYP450-mediated
DDIs for each SSRI

Table 3. The frequencies and percentages of potentially CYP450-mediated
DDIs in category D\&C

Table 4. The most five prescribed potentially interacted drug
combinations and affected CYP450 isozymes for category D\&C

Table 5. The frequencies and percentages of affected CYP450 isozymes in
the prescriptions with pDDIs

Table 6. The frequencies and percentages of the most frequently
potentially CYP450-interacted drugs with SSRIs and alternative SSRIs for
remove CYP450-mediated DDIs

Figure 1. The most frequently potentially CYP450-mediated interacted
drug groups with SSRIs

Supplemental dataset

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\verb`Figure 1.docx`  available at \url{https://authorea.com/users/470991/articles/562760-potential-cytochrome-p450-mediated-drug-drug-interactions-with-selective-serotonin-reuptake-inhibitors-a-retrospective-analysis-of-a-university-hospital-prescription-database}

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\verb`Table 1.docx`  available at \url{https://authorea.com/users/470991/articles/562760-potential-cytochrome-p450-mediated-drug-drug-interactions-with-selective-serotonin-reuptake-inhibitors-a-retrospective-analysis-of-a-university-hospital-prescription-database}

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\verb`Table 2.docx`  available at \url{https://authorea.com/users/470991/articles/562760-potential-cytochrome-p450-mediated-drug-drug-interactions-with-selective-serotonin-reuptake-inhibitors-a-retrospective-analysis-of-a-university-hospital-prescription-database}

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\verb`Table 3.docx`  available at \url{https://authorea.com/users/470991/articles/562760-potential-cytochrome-p450-mediated-drug-drug-interactions-with-selective-serotonin-reuptake-inhibitors-a-retrospective-analysis-of-a-university-hospital-prescription-database}

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\verb`Table 4.docx`  available at \url{https://authorea.com/users/470991/articles/562760-potential-cytochrome-p450-mediated-drug-drug-interactions-with-selective-serotonin-reuptake-inhibitors-a-retrospective-analysis-of-a-university-hospital-prescription-database}

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\verb`Table 5.docx`  available at \url{https://authorea.com/users/470991/articles/562760-potential-cytochrome-p450-mediated-drug-drug-interactions-with-selective-serotonin-reuptake-inhibitors-a-retrospective-analysis-of-a-university-hospital-prescription-database}

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\verb`Table 6.docx`  available at \url{https://authorea.com/users/470991/articles/562760-potential-cytochrome-p450-mediated-drug-drug-interactions-with-selective-serotonin-reuptake-inhibitors-a-retrospective-analysis-of-a-university-hospital-prescription-database}

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