Genotyping of patients treated with selective serotonin reuptake inhibitors

Vigdis Solhaug; Tore Haslemo; Marianne Kristiansen Kringen; Espen Molden; Erik Sveberg Dietrichs

doi:10.4045/tidsskr.22.0017

Original article

Genotyping of patients treated with selective serotonin reuptake inhibitors

Norwegian

Vigdis Solhaug, Tore Haslemo, Marianne Kristiansen Kringen, Espen Molden, Erik Sveberg Dietrichs

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Vigdis Solhaug

Centre for Psychopharmacology

Diakonhjemmet Hospital

Author contribution: data collection, drafting of the manuscript.

Vigdis Solhaug MSc Pharm, role involves advising on and interpreting pharmacogenetic analyses and drug analyses.

The author has completed the ICMJE form and declares no conflicts of interest.

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Tore Haslemo

Centre for Psychopharmacology

Diakonhjemmet Hospital

and

Oslo Metropolitan University

Author contribution: interpretation, drafting of the manuscript.

Tore Haslemo, head of department and associate professor.

The author has completed the ICMJE form and declares no conflicts of interest.

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Marianne Kristiansen Kringen

Centre for Psychopharmacology

Diakonhjemmet Hospital

and

Oslo Metropolitan University

Author contribution: method development, drafting of the manuscript.

Marianne Kristiansen Kringen, head of the pharmacogenetic analysis unit and associate professor.

The author has completed the ICMJE form and declares no conflicts of interest.

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Espen Molden

Centre for Psychopharmacology

Diakonhjemmet Hospital

and

Department of Pharmacy

University of Oslo

Author contribution: interpretation, drafting of the manuscript.

Espen Molden, head of the research unit and professor.

The author has completed the ICMJE form and declares no conflicts of interest.

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Erik Sveberg Dietrichs

Orcid

erik.sveberg.dietrichs@uit.no

Centre for Psychopharmacology

Diakonhjemmet Hospital

and

Department of Medical Biology

UiT The Arctic University of Norway

Author contribution: idea, data collection, interpretation, drafting of the manuscript.

Erik Sveberg Dietrichs, senior consultant, associate professor and head of the research group for experimental and clinical pharmacology.

The author has completed the ICMJE form and declares no conflicts of interest.

Abstract

BACKGROUND

Selective serotonin reuptake inhibitors (SSRIs) are used by over 180,000 people in Norway. The enzymes CYP2D6 and CYP2C19 are key in the metabolism of SSRI antidepressants. The serotonin transporter coded by SLC6A4 may be significant for the efficacy of the drugs.

MATERIAL AND METHOD

All patients who had undergone genotyping for CYP2D6, CYP2C19 and SLC6A4 at the Centre for Psychopharmacology in 2020 were included, irrespective of indication. For those patients where data were available, CYP2C19 genotype was linked to serum concentration measurement of escitalopram, which is the most commonly used SSRI drug.

RESULTS

Out of 3,492 patients, 432 (12.4 %) had a combination of genotypes of CYP2D6, CYP2C19 and SLC6A4 considered to lead to the most favourable metabolism and efficacy of SSRI antidepressants. The dose requirement in patients with poor CYP2C19 metabolism was more than halved to achieve the same concentration of escitalopram compared to patients with normal metabolism.

INTERPRETATION

Our findings demonstrate the low prevalence of the most favourable genotype combination for response to SSRIs. Genotype combinations probably contribute to the wide variation between individuals in the efficacy of these drugs and the fact that treatment does not produce the desired outcome in many patients.

Article

Introduction

In 2020, more than 180,000 people in Norway used a selective serotonin reuptake inhibitor (SSRI), and the majority of these used escitalopram (1). SSRI drugs work by inhibiting the reuptake of serotonin in serotonergic synaptic clefts and entail a lower risk of toxic reactions and adverse effects than tricyclic antidepressants (TCA) (2). Escitalopram also has fewer anticholinergic effects than tricyclic antidepressants, making it suitable for older patients. The widespread use of SSRIs can also be attributed to the fact that the drugs are indicated for anxiety (3) and other mental health disorders.

However, the effects associated with the use of SSRIs are not all favourable. Sexual dysfunction is common in both women and men (4), and high doses of citalopram and escitalopram are contraindicated due to the risk of arrhythmias (5). There are also concerns about an initial increase in attempted suicide (3), although some studies indicate the opposite (6). Adverse effects are generally associated with high serum concentrations. Patients with impaired elimination and resulting high serum concentrations of escitalopram switch to other antidepressant treatment to a much greater extent than patients with normal metabolism (7). SSRIs are eliminated via metabolism in the liver, by enzymes in the CYP450 system, with CYP2D6 and/or CYP2C19 being key for all SSRIs (Table 1). There are several different alleles (variants) of the genes that code for these CYP enzymes. Various combinations of CYP alleles determine the genotype, which in turn can be categorised by enzyme activity and thus effect on drug metabolism and serum concentrations of SSRIs. This activity is the phenotype and is classified as normal, ultra-rapid, intermediate or poor metabolism. Similarly to the dosage of the SSRIs, a patient's phenotype will have consequences for serum concentrations (7).

Table 1

Active substance, trade name, metabolic pathway and reference range for serum concentrations of different SSRIs.

Active substance	Best known trade name	Metabolic pathway	Reference range
Escitalopram	Cipralex	CYP2C19 (CYP2D6 and CYP3A4 are involved to a lesser extent)	20–120 nmol/L
Citalopram	Cipramil	CYP2C19 (CYP2D6 and CYP3A4 are involved to a lesser extent)	70–350 nmol/L
Sertraline	Zoloft	CYP2C19 (CYP3A4, CYP2B6, CYP2C9 and CYP2D6 as well as UGT are involved to a lesser extent)	20–250 nmol/L
Paroxetine	Seroxat	CYP2D6	40–400 nmol/L
Fluoxetine	Fontex	Partly CYP2D6 and CYP2C9 (CYP3A4 and CYP2C19 are involved to a lesser extent)	400–2,500 nmol/L
Fluvoxamine	Fevarin	Partly CYP2D6 and CYP1A2	60–900 nmol/L

Even with normal metabolism of SSRIs, it is not guaranteed that the patient will have the anticipated effect from treatment. Since these drugs work by inhibiting reuptake of serotonin in the synapses, the amount of target protein (serotonin transporter) will be significant for efficacy. The gene SLC6A4 codes for the serotonin transporter. The regulatory region 5-HTTLPR in this gene can be present as a short (S) or long (L) variant, which influences levels of serotonin transporter. Two alleles of the short variant (S/S) cause low levels and an increased risk of lack of efficacy of SSRIs compared to the allele combinations causing high (L/L) or intermediate (S/L) levels of serotonin transporter (8–10). The L/L genotype will produce the most favourable effect, while the S/L genotype is considered to lead to an adequate effect of SSRIs. In addition, the S/L genotype is most common in most populations, and therefore documentation about efficacy and recommended dosage is largely based on this subgroup.

In order to optimise treatment with an SSRI, it would be useful to have phenotype information for both CYP enzymes and the serotonin transporter. The objective of this study was to investigate the proportion of our patient population that has the most favourable phenotype combination of CYP2D6, CYP2C19 and serotonin transporter, as well as to investigate the relationship between phenotype and serum concentration of the most commonly used SSRI drug, escitalopram.

Material and method

This retrospective cross-sectional study was conducted in the Centre for Psychopharmacology at Diakonhjemmet Hospital in Oslo following approval from the hospital's data protection officer. Data about serum concentration measurements and pharmacogenetic analyses were obtained from an internal drug monitoring database for patients who had undergone CYP2D6, CYP2C19 and SLC6A4 genotyping from 1 January 2020 to 31 December 2020. The indication for pharmacogenetic analysis included lack of efficacy or adverse effects with various medications (mainly psychotropic drugs) and wish for genotyping before the start of treatment to investigate which medications would be most suitable for the patient. There was a lack of information about the indication in the request for a large proportion of the tests.

We wanted to investigate escitalopram metabolism in the genotyped patients. Therefore, we identified escitalopram concentrations in the included patients measured in the period 1 January 2019 to 31 December 2020. The data were linked and then anonymised, and the linking key and personal data were deleted on publication. The genotyping methods have been described in detail previously (7). After genotyping of the most relevant variant alleles for CYP2D6 and CYP2C19, the patients were classified into various phenotypes according to normal, ultra-rapid, intermediate or poor metabolism (often referred to with the abbreviations NM, UM, IM and PM respectively) based on standard analysis practice in our laboratory (see www.pharmgkb.org for updated list). Together with genotype of the gene that codes for the serotonin transporter (L/L, S/L or S/S) and measured serum concentrations, this forms the basis of the feedback given to the requesting doctor.

For each test result, the requesting doctor was informed in writing about whether the serum concentration was as expected based on the dosage and, if applicable, given advice about changes to the treatment regimen. Serum concentrations within the reference range are expected to produce a clinical effect since the reference values have been drawn up based on use of therapeutic doses in the normal population. In the event of extremely high levels, the requesting doctor was alerted by telephone and advised to reduce the dose, discontinue treatment or monitor the patient closely, depending on the drug, comorbidities and other circumstances. Intoxication tests were excluded from this material. We have no information about the consequences of the test results or whether the patients were being treated with medications that may have caused interactions with escitalopram.

A total of 6,069 patients over the age of 16 years underwent genotyping for both CYP2D6 and CYP2C19, while 3,492 also underwent genotyping for SLC6A4, which codes for the serotonin transporter. The data were linked with serum escitalopram concentration measurements. The time of the last dose and sampling time had to be listed, and only samples taken 12–24 hours after the last dose of escitalopram were included. Null values and presumed intoxication tests (> 250 nmol/L), as well as samples where the stated dose was over 60 mg or not stated, were excluded. Our material thus contained 287 patients with measured concentrations of escitalopram. In cases where there were several available serum concentration measurements from the same patient, one random concentration was chosen from each patient.

Escitalopram is predominantly metabolised by the enzyme CYP2C19. The relationship between serum concentration and dose (C/D ratio) was calculated to work out which dosage should be recommended for the individual patient according to CYP2C19 phenotype.

Statistics

The data were examined with the Shapiro-Wilks test, which showed that they were not normally distributed. Comparisons of serum concentration, dosage and predicted dose requirement in escitalopram patients with various CYP2C19 phenotypes were therefore performed with a nonparametric test (Kruskal-Wallis test), with Dunn's method as post-hoc analysis.

Results

The 6,069 CYP2D6 analyses performed revealed that 3,325 patients (54.8 %) had normal metabolism, 2,232 (36.8 %) had intermediate metabolism, 365 (6.0 %) had poor metabolism and 147 (2.4 %) had ultra-rapid metabolism. Corresponding figures for CYP2C19 were 3,974 (65.5 %), 1,643 (27.1 %), 196 (3.2 %) and 256 (4.2 %). The analyses of SLC6A4 revealed that 1,683 (48.2 %) patients had intermediate levels of the serotonin transporter (S/L genotype), while 1,152 (33.0 %) had high levels (L/L genotype) and 657 (18.8 %) low levels (S/S genotype).

The phenotype for normal metabolism for both CYP2D6 and CYP2C19 as well as high levels of serotonin transporter (L/L genotype) was found in 442 patients (12.4 %) (Figure 1).

A total of 3,174 patients (87.6 %) had one or more phenotypes of CYP2D6, CYP2C19 and/or the serotonin transporter indicative of an effect to a greater or lesser extent on the efficacy and/or metabolism of some or all SSRIs. In all, 56 patients (1.6 % of patients genotyped for CYP2D6, CYP2C19 and SLC6A4) had low levels of the serotonin transporter and a phenotype for poor metabolism via CYP2D6 and/or CYP2C19. Among the 2,744 patients with poor, intermediate or ultra-rapid CYP2D6 enzyme activity, 1,802 (29.7 % of the 6,069 patients tested) had normal CYP2C19 enzyme activity. Among patients with poor, intermediate or ultra-rapid CYP2C19 enzyme activity, 1,153 (19.0 % of the 6,069 patients tested) had normal CYP2D6 enzyme activity.

The median serum concentration of escitalopram was 47.0 nmol/L in patients with the phenotype normal metabolism for CYP2C19 (n = 202), 66.0 nmol/L in patients with intermediate metabolism (n = 64), and 133 nmol/L in patients with poor metabolism (n = 7) (Figure 2). The mean concentration (SD) was 60.7 nmol/L (50.9), 75.2 nmol/L (47.4) and 142 nmol/L (65.7) respectively. There was a statistically significantly difference in the distribution of serum concentration values in the groups with intermediate and poor metabolism respectively compared to the distribution in the group with normal metabolism (p-value of 0.013 and <0.001 respectively). There was no significant difference between the group with normal metabolism and the group with ultra-rapid metabolism. There were no differences in daily dose between the groups.

Based on estimates of median C/D ratio in patients in the different groups, we were able to calculate the dose required to achieve the same serum concentrations as the group with normal enzyme activity (Table 2). The predictions indicated that the groups with intermediate and poor metabolism had significantly lower dose requirements than the group with normal metabolism. There was no significant difference between the groups with normal and ultra-rapid metabolism. All the patients with poor metabolism via CYP2C19 whose escitalopram concentrations had been measured either had intermediate or normal metabolism via CYP2D6. There was no difference in age between the phenotype groups.

Table 2

CYP2C19 phenotype and dosage of escitalopram. Calculated dose of escitalopram to achieve the same serum concentrations as the normal metabolism group for various phenotypes of CYP2C19, based on the findings in this study.

CYP2C19 phenotype	Concentration/dose ratio, median (nmol/mg)	Change in required dose from normal phenotype (%)	Equivalent to 5 mg for normal phenotype (mg)	Equivalent to 10 mg for normal phenotype (mg)	Equivalent to 20 mg for normal phenotype (mg)
Normal metabolism	3.4	0	5.0	10.0	20.0
Intermediate metabolism	5.1	−34	3.3	6.6	13.2
Poor metabolism	9.2	−63	1.8	3.7	7.3
Ultra-rapid metabolism	3.2	+5	5.3	10.6	21.1

Discussion

In this study, we found that a patient with an assessed need for genotyping in connection with drug treatment is most likely to have normal metabolism via CYP2D6 or CYP2C19, which are the primary enzymes in the metabolism of serotonin reuptake inhibitors. One-third of patients also have high levels of serotonin transporter in the synapses. Only 12.4 % of patients in our study had the phenotype for normal enzyme activity for both the CYP enzymes as well as high levels of serotonin transporter.

More than two-thirds of patients in our study had a phenotype that suggests intermediate or poor metabolism via CYP2D6 or CYP2C19, as well as high or intermediate levels of serotonin transporter. In this group of patients, genotyping would be able to provide useful information because the majority of these patients had normal activity for the other key SSRI-metabolising CYP enzyme (CYP2D6/CYP2C19). Therefore, it is possible that a patient with adverse effects or therapeutic failure with, for instance, escitalopram (CYP2C19) and functional serotonin transporter may benefit from switching to an SSRI primarily metabolised by the CYP2D6 enzyme. Therefore, genotyping may be a useful supplement to serum concentration measurements in order to personalise treatment and reduce the risk of adverse effects and therapeutic failure.

Use of the Hamilton depression scale has shown an increased response rate to treatment with escitalopram when there are high serotonin transporter levels compared to intermediate and very low levels (11). Therefore, it could be assumed at the start of treatment with an SSRI that the L/L genotype of SLC6A4 in combination with normal metabolism of the relevant drug by CYP2C19/CYP2D6 is most favourable. However, as our study shows, most patients have intermediate serotonin transporter levels, and this is still considered to lead to an adequate clinical effect from SSRIs. Therefore, the clinical benefit of genotyping SLC6A4 is not entirely clear since the S/S genotype does not cause a complete lack of serotonin transporter either. Consequently, an analysis result revealing the S/S genotype does not rule out efficacy for all SSRIs (12) and must never override clinical assessment of treatment response, despite several meta-analyses and review articles demonstrating that patients with SLC6A4 genotype S/S have less favourable treatment outcomes (8–10).

Rationally, other types of antidepressants should nonetheless be considered in preference to SSRIs if it is known that the patient has the S/S genotype of SLC6A4. The small group of patients who have the phenotype for poor CYP2D6 and/or CYP2C19 metabolism in addition to low serotonin transporter levels (S/S) are likely to be particularly susceptible to adverse effects. In total, only 8.2 % (n = 56) of patients with the S/S genotype of SLC6A4 in our study were in this category. Contrary to the case for use of SSRIs such as escitalopram (7, 9), no association was found in one study between decreased serotonin transporter levels and efficacy of treatment with the SNRI (serotonin and noradrenaline reuptake inhibitor) duloxetine (13). Depending on the indication and clinical presentation, other antidepressants that do not exclusively work via the serotonin transporter, e.g. vortioxetine, venlafaxine, bupropion, mirtazapine and mianserin, may also be appropriate alternatives.

Due to QT prolongation and the risk of serious arrhythmias (5, 14–16), the maximum recommended daily dose of escitalopram is 20 mg. It is natural to assume that patients in the group with poor metabolism have a much higher risk of these adverse effects, since at any given dose they will have serum escitalopram concentrations almost three times higher than concentrations in patients in the group with normal metabolism. Some studies suggest that the difference between the groups with poor and normal metabolism is even greater (17). Given the risk of ventricular arrhythmias and sudden cardiac death (15), it is important to prevent serum concentrations reaching toxic levels, even with the use of normal doses. Therefore, it is advisable to adjust escitalopram dosage based on CYP2C19 phenotype (Table 2) and to monitor with serum concentration measurements. In this way, the risk of serious adverse effects can be reduced. Patients with a phenotype that suggests ultra-rapid or normal metabolism often require higher doses than patients with intermediate or poor metabolism (17).

Another serious and very common adverse effect of SSRIs is sexual dysfunction. There may be an effect on arousal, libido, orgasm and ejaculation, with an overall prevalence of between 25 % and 73 % of patients. These adverse effects can lead to decreased adherence to treatment, and many patients are reluctant to talk to their doctor about sexual adverse effects (18). Since these adverse effects can be dose-related (19), patients with intermediate or poor CYP2D6 and/or CYP2C19 metabolism will probably be at increased risk if they are being treated with an SSRI metabolised by the relevant enzyme. These patients would benefit from adjustment of their SSRI treatment to the CYP phenotype.

As well as there being a clear difference in serum concentrations of escitalopram between the phenotypes with normal, intermediate and poor CYP2C19 metabolism, there is wide variation within the groups. In our study, this is particularly apparent in the group with increased enzyme activity, in which two patients had unexpectedly high serum concentrations of over 150 nmol/L. On one hand, this shows that the phenotypes include a heterogeneous range of genotypes, and that hitherto unknown variants may exist which cause different enzyme activity than is currently known about and which are reflected in serum concentrations. On the other hand, it shows that genotyping alone cannot predict serum concentrations (and thus efficacy of treatment) or the risk of adverse effects in patients, which is demonstrated, for instance, by the fact that the number of SSRI serum concentration measurements above the upper limit of the reference range are two-fold higher in patients aged 60 years or older compared with patients younger than 60 years (20).

It is possible that our patient material consists of patients who have an abnormal effect from escitalopram, and therefore it has a different distribution of genotypes than the average population. However, frequency studies with European patients demonstrate figures consistent with the data in our study (21, 22). Nevertheless, this may change over time because migration may change the prevalence of various CYP genotypes (23). Our material from genotyped patients originates from a group with far wider indications for genetic testing than treatment with SSRIs because these tests may be appropriate during treatment or before initiating treatment with a wide variety of drugs. Therefore, the selection is as relevant as it is possible to get in a retrospective study from normal clinical practice. Nevertheless, genotyping alone cannot be used to predict efficacy of treatment of SSRIs, and in our material this particularly applies to patients with ultra-rapid metabolism. To be able to give accurate recommendations about dosage of SSRIs, we require more information about other factors that can affect the bioavailability and elimination of drugs from the body. In addition to metabolising enzymes and age, serum concentrations are also affected by weight, sex, renal function, hepatic function, bowel disease, interactions with other drugs and a number of other factors. Several SSRIs can also inhibit the metabolism of other drugs. Therefore, systematised clinical information may improve patient treatment and lead to a decrease in the number of drug-related hospital admissions. This is important because this patient group accounts for up to 20 % of all admissions to Norwegian emergency departments (24).

Conclusion

A small proportion of patients in the study had the phenotype combination of the enzymes CYP2D6 and CYP2C19 and the serotonin transporter coded by SLC6A4 that is most favourable for treatment with the six SSRI drugs on the market in Norway. Knowing the individual patient's phenotypes offers the potential to optimise treatment and reduce the risk of adverse effects when SSRIs are prescribed.

The article has been peer-reviewed.

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Comments ( 5 )

Dette kommentarfeltet modereres, men kommentarer blir ikke redaksjonelt behandlet ut over å sikre at de følger retningslinjer for vårt kommentarfelt.

06.10.2022:

Takk til Solhaug og medforfattere for å tematisere den utstrakte bruken av SSRI i Norge, og for å presentere fenotyping av enzymene CYP2D6 og CYP2C19 og serotonintransportøren SLC6A4 som et mulig alternativ for å redusere bivirkninger av denne bruken (1). Forfatternes budskap er i korte trekk følgende; hvis du har genotyper som metaboliserer SSRI dårlig får du høyere plasmakonsentrasjon av SSRI med større sjanse for bivirkninger.

At suboptimal genotype CYP2D6/CYP2C19 gir høyere plasmakonsentrasjon av SSRI er godt dokumentert (1,2). I tillegg til metaboliseringen av SSRI vil genotypen til serotonintransportøren SLC6A4 påvirke mengden serotonin som er tilgjengelig i synapsespalten. En genotype som koder for den korte varianten (S/S) gir liten mengde transportører og økt risiko for mangelfull effekt av SSRI-preparater, sammenliknet med allelkombinasjonene som gir stor (L/L) eller intermediær (S/L). Logikken er at færre serotonintransportører gir færre målproteiner for SSRI-preparatene å virke på.

Samlet vil pasienter med suboptimale genotyper ha høyere nivåer av SSRI i forhold til de med optimal kombinasjon av genotypene CYP2D6, CYP2C19 og SLC6A4.

Så til bakgrunnen for min kommentar. At serotonin påvirker humøret i en eller annen grad er ingen kontroversiell påstand, men det er derimot den originale serotonin-hypotesen om depresjon. En ny oversikt over systematiske oversikter, en såkalt paraplyoversikt av Moncrieff et al (3) konkluderer med følgende:

«Hovedområdene i serotoninforskningen gir ikke konsistente bevis for en sammenheng mellom serotonin og depresjon, og gir heller ingen støtte for hypotesen om at depresjon skyldes mindre serotoninaktivitet eller senkede nivåer av serotonin. Noe bevis peker i retning av at langtidsbruk av antidepressiva senker serotoninnivået.» (min oversettelse).

Jeg synes det er viktig å påpeke dette slik at artikkelen til Solhaug og medforfattere ikke blir tatt til inntekt for den seiglivete serotonin-hypotesen, men heller som et viktig bidrag i debatten om fenotypingens rolle i optimal pasientbehandling.

Litteratur
1. Solhaug V, Haslemo T, Kringen MK et al. Genotyping av pasienter behandlet med selektive serotoninre¬opptakshemmere. Tidsskr Nor Legeforen 2022; 142. doi: 10.4045/tidsskr.22.0017

2. Grasmäder K, Verwohlt PL, Rietschel M et al. Impact of polymorphisms of cytochrome-P450 isoenzymes 2C9, 2C19 and 2D6 on plasma concentrations and clinical effects of antidepressants in a naturalistic clinical setting. Eur J Clin Pharmacol. 2004 Jul;60(5):329-36.

3. Moncrieff J, Cooper RE, Stockmann T et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry (2022).

11.10.2022:

Vi vil takke Morten Svendsen Næss for en relevant kommentar til vår artikkel «Genotyping av pasienter behandlet med selektive serotonin-reopptakshemmere» (1). Som Næss påpeker er ikke vår artikkel ment som en støtte til teorien om at depresjon skyldes mindre serotoninaktivitet eller senkede nivåer av serotonin, men å beskrive hvordan ulike genotyper av CYP2D6, CYP2C19 og serotonintransportøren (SLC6A4) kan påvirke responsen ved SSRI-behandling. At genvarianter i CYP2D6 og CYP2C19 har godt dokumentert betydning for utfall av SSRI-behandling er det bred enighet om. I denne sammenhengen er det imidlertid på sin plass å presisere at den hittil største meta-analysen som har undersøkt korrelasjon mellom SLC6A4 promotergenotype og klinisk respons av SSRI-behandling, viser en signifikant sammenheng mellom disse variablene, og da spesielt innen europeisk befolkning (2).

Det regulerende området av SLC6A4-genet (5-HTTLPR) kan foreligge i en kort (S) eller lang (L) variant, noe som har betydning for mengden serotonintransportør som blir utrykt. Personer som er homozygote for S-allelet (S/S) har nedsatt mengde serotonintransportører i hjernen, noe som er forenlig med redusert effektpotensial/klinisk respons av behandlingen og dermed støtte for at genotyping av 5-HTTLPR til en viss grad kan predikere behandlingsutfall. Et analysesvar som viser S/S-genotypen, utelukker likevel ikke effekt av alle SSRI-preparater og må aldri overstyre klinisk vurdering av behandlingsrespons (1). Derfor anbefaler vi at SLC6A4-genotyping primært benyttes for å utrede sviktende klinisk effekt under pågående SSRI-behandling.

Det er i overkant av 180 000 pasienter i Norge som bruker SSRI-preparater. Vår artikkel tar ikke for seg hvorvidt dette er et høyt tall, eller det patofysiologiske grunnlaget for behandlingen. Artikkelens formål er snarere å belyse sammenhengen mellom fenotyper av CYP2C19, CYP2D6 og SLC6A4 og risiko for terapisvikt og konsentrasjonsavhengige bivirkninger ved SSRI-behandling hos den enkelte pasient.

Litteratur
1. Solhaug V, Haslemo T, Kringen MK et al. Genotyping av pasienter behandlet med selektive serotoninreopptakshemmere. Tidsskr Nor Legeforen 2022; 142. doi: 10.4045/tidsskr.22.0017
2. Stein K, Al Maruf A, Müller DJ et al. Serotonin Transporter Genetic Variation and Antidepressant Response and Tolerability: A Systematic Review and Meta-Analysis. J Pers Med. 2021 Dec 1;11(12).

18.10.2022:

Vigdis Solhaug og medarbeidere har lagt ned en betydelig arbeidsinnsats for å beskrive og måle biologiske mekanismer som kan medføre endringer i serumkonsentrasjoner av selektive serotoninreopptakshemmere (SSRI) (1). Artikkelen bygger på noen forutsetninger som er upresist og til dels feilaktig gjengitt.

Utgangspunktet for artikkelen er en postulert sammenheng mellom serumkonsentrasjon av SSRI og behandlingseffekt, altså at det finnes terapeutiske vinduer hvor serumkonsentrasjoner er over nivåer assosiert med terapisvikt, men under nivåer som resulterer i en uakseptabel frekvens av bivirkninger. Forskningslitteraturen kan ikke bekrefte denne antakelsen.

I tillegg synes Solhaug og medarbeidere å mene at laboratoriet har avklart hva den effektive serumkonsentrasjonen - som omtales som "referanseverdien" (1) - faktisk er. Den er "... utarbeidet ut fra bruk av terapeutiske doser i normalbefolkningen " (1). Dette er et sirkelargument, en eufemisme som rent praktisk består av å regne ut et matematisk gjennomsnitt med standardavvik av mottatte prøver, uten noen form for registrering eller vurdering av behandlingseffekt. Blodprøver som rutinemessig innsendes til farmakologiske laboratorier for konsentrasjonsbestemmelser inneholder sjelden opplysninger om terapieffekt. Systematisk innhentede opplysninger om legemiddeleffekter er i slike sammenhenger totalt fraværende.

Den eneste grunnen til å måle serumkonsentrasjoner av SSRI er for å avklare om pasienten har tatt et SSRI. Det kan være nyttig å vite, særlig ved mistanke om overdose.

Litteratur
1. Solhaug V, Haslemo T, Kringen MK et al. Genotyping av pasienter behandlet med selektive serotoninreopptakshemmere. Tidsskr Nor Legeforen 2022; 142. doi:10.4045/tidsskr.22.0017

25.10.2022:

I likhet med en kommentar publisert i 2009 av samme forfatter, antydes det her at dosen av antidepressiver i prinsippet ikke er av betydning for den kliniske responsen pasienten opplever (1). I det vitenskapelige miljøet er det allment akseptert at serumkonsentrasjon er et bedre mål på eksponering for medikament på virkestedet enn det dosen er, ettersom det er store inter- og intraindividuelle forskjeller i opptak, metabolisme og andre farmakokinetiske prosesser. Resultatet er at serumkonsentrasjonen varierer for samme dosering (2). Hvis slike forskjeller ikke fantes, ville legemidler i prinsippet kunne doseres likt hos alle pasienter med samme sykdom.

Evidensen for at serumkonsentrasjon av antidepressiver, inkludert SSRI, er knyttet til klinisk respons er enda bedre i dag enn den var for 13 år siden. Vår forskningsgruppe har blant annet publisert store studier i American Journal of Psychiatry og Journal of Clinical Psychopharmacology. Som forventet viste studiene at serumkonsentrasjon av escitalopram (3) og vortioksetin (4) er avgjørende for utfall av behandling og direkte relatert til den enkelte pasients CYP-genotype. I tillegg vil faktorer som alder, kjønn, lever- og nyrefunksjon, graviditet, og annen samtidig legemiddelbehandling påvirke serumkonsentrasjonen og dermed effekt/risiko for bivirkninger av behandlingen.

Gjerden har et poeng i at serumkonsentrasjonsmålinger også er av verdi for å få et bilde av doseinntak, både ved mistanke om overdosering og kanskje enda viktigere ved indikasjon på manglende etterlevelse. Vi har nylig vist i en studie på mer enn 13.000 pasienter at om lag 5% ikke har målbare nivåer av antipsykotiske legemidler, til tross for at disse har blitt forskrevet (5). Andre studier viser enda lavere etterlevelse.

Vi er altså uenig i at serumkonsentrasjonsmålinger kun er aktuelt for å avklare om pasienten har tatt et SSRI og mener det er godt dokumentert at serumkonsentrasjon har betydning for både effekt og bivirkninger av behandlingen.

Litteratur
1. Gjerden P. Unyttige psykofarmakologiske analyser. Dagens Medisin. 18.9.2009. https://www.dagensmedisin.no/artikler/2009/09/18/unyttige-psykofarmakologiske-analyser/?x=MjAxNy0wMi0wNSAwMjoyNzowNA==&x=MjAxNy0wMi0wNSAwMjoyNzowNA== Lest 25.10.22.
2. Solhaug V, Haslemo T, Kringen MK et al. Genotyping av pasienter behandlet med selektive serotoninreopptakshemmere. Tidsskr Nor Legeforen 2022; 142. doi: 10.4045/tidsskr.22.0017
3. Jukić MM, Haslemo T, Molden E et al. Impact of CYP2C19 Genotype on Escitalopram Exposure and Therapeutic Failure: A Retrospective Study Based on 2,087 Patients. Am J Psychiatry. 2018;175(5):463–70.
4. Frederiksen T, Smith RL, Jukic MM et al. Association Between CYP2D6 Metabolizer Status and Vortioxetine Exposure and Treatment Switching: A Retrospective, Naturalistic Cohort Study Using Therapeutic Drug Monitoring Data From 640 Patients. J Clin Psychopharmacol. 2022;42(4):396–9.
5. Smith RL, Tveito M, Kyllesø L et al. Rates of complete nonadherence among atypical antipsychotic drugs: A study using blood samples from 13,217 outpatients with psychotic disorders. Schizophr Res. 2021;228:590–6.

31.10.2022:

Dietrichs og medarbeidere har helt rett når de skriver at "det er store inter- og intraindividuelle forskjeller i opptak, metabolisme og andre farmakokinetiske prosesser. Resultatet er at serumkonsentrasjonen varierer for samme dosering" (1). Andre sentrale farmakokinetiske prosesser for psykofarmaka inkluderer transport over blod-hjerne barriéren og grad av binding til målstrukturer i sentralnervesystemet, altså prosesser som for slike midler fremstår som langt mer sentrale og avgjørende enn serumnivå. Dette betyr igjen at effekten ikke bare varierer med samme dosering, men også med samme serumkonsentrasjon. Mange av prosessene som styrer dette - for ikke å si selve den grunnleggende mekanismen som ligger bak utviklingen av depresjonslidelser - er fremdeles mangelfullt eller lite kjent. Serotoninhypotesen - at depresjon skyldes lav serotoninaktivitet eller konsentrasjon - savner dokumentasjon (2). Dette innbyr til ydmykhet og undring.

Dietrichs og medarbeidere hevder i sitt tilsvar til meg å ha vist i to studier at "serumkonsentrasjon av escitalopram (3) og vortioksetin (4) er avgjørende for utfall av behandling ..." I begge studiene er endepunktet persistens med hhv. escitalopram eller vortioksetin; skifte til et annet antidepressiv innen en gitt tid (som i de to studiene varierer fra 3 mndr til ett år) utlegges som terapisvikt. Dette skjer på en bakgrunn hvor bruk av forskjellige kvantitative diagnostiske skalaer er utbredt både for å stille depresjonsdiagnosen og for å overvåke behandlingsresponsen, men - i denne sammenhengen - ikke for å differensiere respondere fra non-respondere. Forstå det den som kan. I mitt hode har debatten medført - og ønsket går både til Dietrichs og medarbeidere og mange andre kolleger - et ønske om en større grad av intellektuell redelighet. For dette er ingen selskapslek. Vi diskuterer pasienter med et høyt lidelsestrykk og en betydelig mortalitet.

Litteratur
1. Dietrichs ES, Solhaug V, Haslemo T et al. E. S. Dietrichs og medarbeidere svarer P. Gjerden. Tidsskr Nor Legeforen. https://tidsskriftet.no/2022/10/kommentar/e-s-dietrichs-og-medarbeidere-svarer-p-gjerden#comment-2716 Lest 31.10.2022.
2. Moncrieff J, Cooper RE, Stockman T et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Molecular Psychiatry 2022. https://doi.org/10.1038/s41380-022-01661-0
3. Jukié MM, Haslemo T, Molden E et al. Impact of CYP2C19 genotype on escitalopram exposure and therapeutic failure: A retrospective study based on 2,087 patients. Am J Psychiatry 2018; 175(5): 463-70
4. Fredriksen T, Smith RL, Jukié MM et al. Association between CYP2D6 metabolizer status and vortioxetine exposure and treatment switching: A retrospective, naturalistic cohort study using therapeutic drug monitoring data from 640 patients. J Clin Psychopharmacol 2022; 42(4): 396-9

This article was published more than 12 months ago and we have therefore closed it for new comments.

Published: 26 September 2022

Tidsskr Nor Legeforen 26 September 2022 Vol. 142.

doi:

10.4045/tidsskr.22.0017

Received 5.1.2022, first revision submitted 21.4.2022, accepted 10.8.2022.

Open access CC-BY-ND
Copyright: The author(s)

Published: 26 September 2022

Tidsskr Nor Legeforen 2022 Vol. 142.

doi: 10.4045/tidsskr.22.0017

Received 5.1.2022, first revision submitted 21.4.2022, accepted 10.8.2022.

Open access CC-BY-ND
Copyright: The author(s)

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Genotyping of patients treated with selective serotonin reuptake inhibitors

BACKGROUND

MATERIAL AND METHOD

RESULTS

INTERPRETATION

MAIN FINDINGS

Table 1

Material and method

Statistics

Results

Table 2

Discussion

Conclusion

Genotyping av pasienter behandlet med SSRI

E. S. Dietrichs og medarbeidere svarer

Serumkonsentrasjon av selektive serotoninre-opptakshemmere

E. S. Dietrichs og medarbeidere svarer P. Gjerden

Psykofarmaka virker ikke i serum

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