16 - Chapter 11 Pharmacokinetics

01 - Plasma level monitoring of psychotropic drugs
Plasma level monitoring of psychotropic drugs

02 - First order pharmacokinetics
First-order pharmacokinetics

03 - Steady state
Steady state
The Maudsley® Prescribing Guidelines in Psychiatry, Fifteenth Edition. David M. Taylor,
Thomas R. E. Barnes and Allan H. Young.
© 2025 David M. Taylor. Published 2025 by John Wiley & Sons Ltd.
Chapter 11
Plasma level monitoring of psychotropic drugs
The measurement of blood or plasma drug concentrations is widely known as therapeutic
drug monitoring or TDM. It is often used in psychiatry but not always well used. The
interpretation of drug concentrations (drug ‘levels’) is a complex process that requires a
thorough understanding of pharmacokinetics. Some principles are outlined here.
First-­order pharmacokinetics
The metabolism and excretion of most drugs follow first-­order elimination kinetics.
The key feature of this model is that clearance of a drug is constant when expressed in
volume per unit time – usually L/h. The mass of drug cleared (metabolised or excreted)
increases as blood concentration increases. For example, if clearance of a drug is 10L/h
and the concentration is 5mg/L then 50mg (10×50mg) will be cleared in an hour. If the
concentration increases to 10mg/L then 100mg will be cleared in an hour. The concept
of first-­order pharmacokinetics is important to the understanding of steady state.
Steady state
Repeated dosing of any drug that is not completely removed within the dosing interval
will inevitably lead to accumulation. That is, the second dose will add to what remains
of the first and the third dose will add to what remains of the first and second doses. As
the drug concentration in the blood increases, the mass of the drug cleared will also rise,
according to first-­order principles. Eventually, a point is reached where blood levels
remain stable within a specific peak-to-trough range – this is steady state. It is important
Pharmacokinetics

04 - Timing of sampling
Timing of sampling
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to know when a drug is or is not at steady state but there are two concepts connected
to steady state that are often misunderstood.
■
■Time to reach steady state follows a logarithmic pattern
The time taken to reach steady state is dependent on the drug half-­life – the time
taken for concentration to fall by 50%. This table shows the rise to steady state.
Number of half-­lives
% of steady state reached
75%
87.5%
94%
97%
Most people know the adage that it takes four to five half-­lives to reach steady state.
In fact, three half-­lives are sufficient for an approximation of steady state
concentrations.
■
■Steady state is not always related to therapeutic activity
Blood levels at steady state are determined by dose and drug half-­life. The concentration at which therapeutic activity occurs is fixed (see later) and, during therapeutic
dosing, is often exceeded before steady state is reached. Loading doses are sometimes
used to achieve therapeutic concentrations as quickly as possible. Loading doses do
not hasten the achievement of steady state levels.
Timing of sampling
Sampling time is vitally important for many but not all drugs. If the recommended
sampling time is, say, 12 hours post-­dose, then the sample should be taken 11–13 hours
post-­dose if possible; 10–14 hours post-­dose, if absolutely necessary. A study of clozapine samples taken 1 and 2 hours before and after the 12-­hour scheduled sample time
showed a mean variation of clozapine blood concentration of less than 10%, but some
individuals’ levels varied by over 50%.1 So, if a sample is not taken within 1–2 hours of
the required time, it has the potential to mislead rather than inform. Always try to take
samples as close to the scheduled time as possible. Obviously, if toxicity is suspected,
take a sample straightaway, ignoring any scheduled timings.
For trough or ‘pre-­dose’ samples, take the blood sample immediately before the next
dose is due. Do not, under any circumstances, withhold the next dose for more than
1 or possibly 2 hours until the sample is taken. Withholding for longer than this will
inevitably give a misleading result (it will give a lower result than that ever seen in the
usual, regular dosing), and this may lead to an inappropriate dose increase. Sampling
time is less critical with drugs with a long half-­life (e.g. olanzapine, aripiprazole) but, as
an absolute minimum, prescribers should always record the time of sampling and time
of last dose. This cannot be emphasised enough, and is worth repeating in bold. Always
record the time of sampling and the time of the last dose.

05 - Interpretation of results
Interpretation of results

06 - Target ranges
Target ranges
Pharmacokinetics
CHAPTER 11
Interpretation of results
Is there a target range of plasma levels? If so, then plasma levels (from samples taken at
the right time) will usefully guide dosing. If there is not an accepted target range, plasma
levels can only indicate adherence or potential toxicity. However, if the sample is being
used to check compliance, then bear in mind that a plasma level of zero indicates only
that the drug has not been taken in the past several days. Plasma levels above zero may
indicate erratic compliance, full compliance or even long-­standing non-­compliance disguised by recent taking of prescribed doses. Note also that target ranges have their limitations – patients may respond to lower levels than the quoted range and tolerate levels
above the range. Also, ranges quoted by different laboratories vary sometimes widely,
often without explanation. This is discussed further later.
The basic rule for sample level interpretation is to act upon assay results only in conjunction with reliable clinical observation (‘treat the patient, not the level’). For example, if a patient is responding adequately to a drug but has a plasma level below the
accepted target range, then the dose should not normally be increased. If a patient has
intolerable adverse effects but a plasma level within the target range, then a dose
decrease may be appropriate.
Where a plasma level result is substantially different from previous results, a repeat
sample is usually advised. Check the dose, the timing of dose and recent compliance but
ensure, in particular, the correct timing of the sample, or at the very least that the timing
of sampling is known. Many anomalous results are the consequence of changes in sample timing.
Target ranges
In psychiatry, target ranges for psychotropic drug concentrations should be treated
with some caution. Establishing a range of concentrations associated with response is
made difficult by the presence in trials of non-­responders (who show no response whatever the blood concentration) and by the presence of placebo responders and spontaneous remitters (who respond at any blood concentration). Establishing a target range
based on adverse effects is made difficult by the development of tolerance over time.
Thus, most studies aimed at determining target ranges have as much ‘noise’ as ‘signal’
and results ultimately represent broad approximations.
Interestingly, drug concentrations associated with response in clinical practice
show a fairly close correlation to published target ranges.2 The lower quartile (25th
percentile) of drug concentrations is usually close to the lower end of the target
range and the upper quartile (75th percentile) is around the value of, but usually less
than, the upper limit. Broadly speaking, this means that around 25% of patients
respond below the target range and up to 25% tolerate blood concentrations above
the target range.
The simplicity of published target ranges disguises considerable complexity. For
most drugs, the concentration at which therapeutic activity appears is fairly constant
across a population. This is called the therapeutic threshold – above it, full effect is
seen, but below it, activity is lost. A good example here is risperidone where the
threshold concentration of active moiety is 20mcg/L. Risperidone and paliperidone could
reasonably be considered to have a target concentration rather than a target range of
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CHAPTER 11
concentrations. This concept of a therapeutic threshold is supported by neuroimaging studies. A concentration of 20mcg/L of active moiety is associated with a dopamine occupancy of 65–70%3 – the degree of pharmacological activity associated with
response for most antipsychotics.4 Increasing dopamine occupancy above this level
does not improve efficacy or likelihood of response but does make adverse effects
more likely.3
Clozapine is completely different. For clozapine, the target range represents concentrations usually associated with both response and good tolerability. However, perhaps
10% of responders will improve with clozapine concentrations below the target range
and as many as 20% of responders will only respond at concentrations above the target
range. There is also a so-­called point of futility – the concentration above which no
additional responders will be uncovered. Responders to clozapine will have blood concentrations between 250 and 1000mcg/L5  – a much wider range than the accepted
target range. Unlike risperidone and many other drugs, the threshold concentration is
not fixed across populations.
This subject is eloquently covered in much more detail in The Clinical Use of
Antipsychotic Plasma Levels by Jonathan Meyer and Stephen Stahl (Cambridge
University Press, 2021).
Table 11.1 discusses the interpretation of sample results for various drugs.
Table 11.1  Interpreting sample results for drugs with established target ranges.
Drug
Target range
Sample
timing
Time to
steady state
Comments
Amisulpride
200–320mcg/L
20–60mcg/L (elderly)
Trough
3 days
See text
Aripiprazole
100–210mcg/L
Trough
15–16 days
See text
Carbamazepine6–8
7mg/L
Bipolar disorder
Trough
2 weeks
Carbamazepine induces its own
metabolism. Time to steady state
dependent on auto-­induction
Clozapine
350–600mcg/L
Trough
2–3 days
See text
Lamotrigine9–11
Not established but
suggest 2.5–15mg/L
Trough
5 days
Auto-­induction
is thought to
occur, so time
to steady state
may be longer
Some debate over utility of
lamotrigine levels, especially in
bipolar disorder. In treatment-­
resistant unipolar depression,
plasma levels of above 12.7μmol/L
(3.3mg/L) are associated with
response.12,13 Toxicity may be
increased above 15mg/L but is
normally well tolerated
Lithium14–18
0.6–1.0mmol/L
(0.4mmol may be
sufficient for some
patients/indications;
1.0mmol/L required
for mania)
12 hours
5 days
post-­dose
Well-­established target range, albeit
derived from ancient data sources.
A fairly recent study19 suggested
0.6mmol/L was the minimum level
for a prophylactic effect

07 - Amisulpride
Amisulpride
Pharmacokinetics
CHAPTER 11
Amisulpride
Amisulpride plasma levels are closely related to dose with insufficient variation to make
routine plasma level monitoring prudent. Higher levels observed in women27–29 seem to
have little significant clinical implication for either therapeutic response or adverse
effects. A (trough) threshold for clinical response has been suggested to be approximately 100mcg/L30 and mean levels of 367mcg/L29 have been noted in responders.
Adverse effects (notably extrapyramidal side effects [EPSEs]) occur at mean levels of
336mcg/L,27 377mcg/L30 and 395mcg/L.28 A plasma level threshold of below 320mcg/L
has been found to predict avoidance of EPSEs.30 One review31 has suggested an approximate range of 200–320mcg/L for optimal clinical response and avoidance of adverse
effects but a more recent consensus statement32 suggested a target range of 100–320mcg/L.
A dose of 200mg a day is sufficient to give a blood level of 100mcg/L33 so this lower
threshold is probably too low for a reliable therapeutic effect. In older patients with
Drug
Target range
Sample
timing
Time to
steady state
Comments
Olanzapine
20–40mcg/L
12 hours
1 week
See text
Paliperidone20
20–60mcg/L
(9-­OH risperidone)
Trough
2–3 days oral
2 months
depot
Target range is the same as that
established for risperidone.21 As
with risperidone, routine plasma
level monitoring is not
recommended.
Phenytoin7
10–20mg/L
Trough
Variable
Follows zero-­order kinetics. Free
levels may be useful in some
circumstances.
Quetiapine
Around
50–100mcg/L?
Trough?
2–3 days oral
Target range poorly defined. Plasma
level monitoring not recommended.
See text.
Risperidone
20–60mcg/L
(active moiety –
risperidone + 9-­OH
risperidone)
Trough
2–3 days oral
6–8 weeks
injection
Routine plasma level monitoring is
not recommended. See text.
Tricyclics22
Nortriptyline
50–150mcg/L
Amitriptyline
100–200mcg/L
Trough
2–3 days
Rarely used and of dubious benefit.
Use ECG to assess toxicity.
Valproate6,7,23–25
50–100mg/L
Epilepsy and bipolar
Trough
2–3 days
Some doubt over value of levels in
epilepsy and in bipolar disorder.
Some evidence that, in mania, levels
up to 125mg/L are tolerated and
more effective than lower
concentrations. Valproate plasma
levels are linearly related to plasma
ammonia.26
Table 11.1  (Continued )

08 - Aripiprazole
Aripiprazole

09 - Clozapine
Clozapine
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CHAPTER 11
psychosis, studies suggest plasma concentrations of 20–60mcg/L may give optimal
D2 occupancy and clinical response.34,35
In practice, only a minority of treated patients have ‘therapeutic’ plasma levels (probably because of poor adherence36) so plasma monitoring may be of some benefit.
However, amisulpride plasma level monitoring is rarely undertaken and few laboratories offer amisulpride assays. The dose–response relationship is sufficiently robust (in
trials, at least) to obviate the need for plasma sampling within the licensed dose range
(although in older patients, doses of 50–100mg a day may be sufficient) and adverse
effects are usually well managed by dose adjustment alone. Plasma level monitoring is
best reserved for those in whom clinical response is poor, adherence is questioned or in
whom drug interactions or physical illness may make adverse effects more likely.
Aripiprazole
Plasma level monitoring of aripiprazole is sometimes undertaken in practice. The dose–
response relationship for aripiprazole is well established with a plateau in clinical
response and D2 dopamine occupancy seen in doses above approximately 10mg/day.37
Plasma levels of aripiprazole, its metabolite and the total moiety (parent plus metabolite) strongly relate linearly to dose, making it possible to predict, with some certainty,
an approximate plasma level for a given dose.38 Target plasma level ranges for optimal
clinical response have been suggested as 146–254mcg/L39 and 150–300mcg/L,40 with
adverse effects more frequent above 210mcg/L.40 Inter-­individual variation in aripiprazole plasma levels has been observed but not fully investigated, although gender appears
to have little influence.41,42 Age, metabolic enzyme genotype and interacting medications
seem likely causes of variation.40–43 A putative range of between 150 and 210mcg/L38
has been suggested as a target for patients taking aripiprazole and these are broadly the
concentrations seen in patients receiving depot aripiprazole at 300 and 400mg monthly.44
Some authorities suggest a lower threshold for clinical effect of 100mcg/L32 – a plasma
level usually afforded by an oral dose of 10mg a day33,45 and around the minimum level
reached during treatment with 2-­monthly depot.46
Clozapine
Clozapine plasma levels are broadly related to daily dose47 but there is sufficient variation to make impossible any precise prediction of plasma level. Plasma levels are generally lower in younger patients, males48 and smokers49 and higher in Asians.50 Much
lower doses of clozapine are required in East Asians,51,52 Indians53 and Bangladeshis.54
The prevalence of clozapine poor metabolisers is also higher in East Asians.55,56 A series
of algorithms has been developed for the approximate prediction of clozapine levels
according to patient factors and these are recommended.57 Dose prediction using
genetic analysis is more accurate that algorithm prediction.58 Neither method can
account for other influences on clozapine plasma levels such as changes in adherence,
inflammation59 and infection.60,61
The plasma level threshold for acute response to clozapine has been suggested to be
200mcg/L,62 350mcg/L,63–65 370mcg/L,66 420mcg/L,67 504mcg/L68 and 550mcg/L.69
Limited data suggest a level of at least 200mcg/L is required to prevent relapse.70
Substantial variation in clozapine plasma level may also predict relapse.71 Changes in

10 - Olanzapine
Olanzapine
Pharmacokinetics
CHAPTER 11
an individual’s clozapine plasma levels are common with a tendency for concentrations
to slightly decrease over time,72 although one study suggests a decrease only in norclozapine concentrations.73
Despite these somewhat varied estimates of response threshold, plasma levels can be
useful in optimising treatment. In those not responding to clozapine, the dose should be
adjusted to give plasma levels in the range 350–600mcg/L (a range reflecting a consensus of the above findings32). Those not tolerating clozapine may benefit from a reduction to a dose giving plasma levels in this range. An upper limit to the clozapine target
range has not been defined. Any upper limit must take into account two components:
the level above which no therapeutic advantage is gained and the level at which toxicity/
tolerability is unacceptable. Plasma levels do seem to predict EEG changes74,75 and
­seizures occur more frequently in patients with levels above 1000mcg/L,76 so levels
should probably be kept well below this. Other non-­neurological clozapine-­related
adverse effects also seem to be plasma-­level related77 as might be expected. An upper
limit of concentrations around 600–800mcg/L has been proposed,78 although a level of
1000mcg/L may be the point of futility.79,80
Placing an upper limit on the target range for clozapine levels may discourage potentially worthwhile dose increases within the licensed dose range. Before plasma levels
were widely used, clozapine was sometimes given in doses up to 900mg/day, with valproate being added when the dose reached 600mg/day. It remains unclear whether
using these high doses can benefit patients with plasma levels already above the accepted
threshold. Nonetheless, it is prudent to use an antiseizure agent as prophylaxis against
seizures and myoclonus when plasma levels are above 600mcg/L (a level based more on
repeated recommendation than on being a clear evidence-­based threshold78) and certainly when levels approach 1000μmcg/L.
Norclozapine is the major metabolite of clozapine. The ratio of clozapine to norclozapine averages 1.25  in populations81 but may differ markedly for individuals.82 In
chronic dosing, the ratio should remain the same for a given patient. A decrease in ratio
may suggest enzyme induction, an increase suggests enzyme inhibition, a non-­trough
sample or recent missed doses. Time of sampling radically alters the clozapine/norclozapine ratio as clozapine is relatively high in early samples and norclozapine is higher
in late samples.1 Clozapine metabolism may become saturated at higher doses: the ratio
of clozapine to norclozapine increases with increasing plasma levels, suggesting saturation.83–85 The effect of fluvoxamine also suggests that metabolism via CYP1A2 to norclozapine can be overwhelmed.86
Ultimately, changes in the clozapine/norclozapine ratio may be impossible to interpret. A systematic review concluded that knowledge of clozapine/norclozapine ratio
had no clinical utility.87
Olanzapine
Plasma levels of olanzapine are linearly related to daily dose88 but there is substantial
variation,89 with higher levels seen in women,68 non-­smokers90 and those on enzyme-­
inhibiting drugs.90,91 With once-­daily dosing, the threshold level for response in schizophrenia has been suggested to be 9.3mcg/L (trough sample),92 23.2mcg/L (12-­hour
post-­dose sample)68 and 23mcg/L at a mean of 13.5 hours post-­dose.93 There is evidence
to suggest that levels greater than around 40mcg/L (12-­hour sampling) produce no

11 - Quetiapine
Quetiapine
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further therapeutic benefit than lower levels.94 Severe toxicity is uncommon but may be
associated with levels above 100mcg/L, and death is occasionally seen at levels above
160mcg/L95 (albeit when other drugs or physical factors are relevant). A target range for
therapeutic use of 20–40mcg/L (12-­hour post-­dose sample) has been proposed96 for
schizophrenia; the range for mania is probably similar.97 This target range was for a
time widened to 20–80mcg/L98,99 but the reasons for this were not clear. A 2023 systematic review suggests a target range of 20–40mcg/L for 12-­hour samples.100
Significant weight gain seems most likely to occur in those with plasma levels above
20mcg/L.101 Constipation, dry mouth and tachycardia also seem to be related to plasma
level.102
In practice, the dose of olanzapine should be largely governed by response and tolerability. However, a survey of UK sample assay results suggested that around 20% of
patients on 20mg a day will have sub-­therapeutic plasma levels and more than 40%
have levels above 40mcg/L.103 Plasma level determinations might then be useful for
those suspected of non-­adherence, those showing poor tolerability or those not responding to the maximum licensed dose. Where there is poor response and plasma levels are
below 20mcg/L, dose may then be adjusted to give 12-­hour plasma levels of 20–40mcg/
L; where there is good response and poor tolerability, the dose should be tentatively
reduced to give plasma levels below 40mcg/L. Changes in dose give proportionate
changes in plasma levels.104 A case might be made to increase the dose to give blood
levels in the range 40–80mcg/L but only where no other options remain.
Quetiapine
Doses of quetiapine are weakly related to trough plasma samples.105 Mean levels
reported within the dose range 150–800mg/day vary from 27 to 387mcg/L,106–111
although the highest and lowest levels are not necessarily found at the lowest and highest doses. Age, gender and co-­medication may contribute to the significant inter-­
individual variance observed in TDM studies, with female gender,111,112 older age110,111
and CYP3A4-­inhibiting drugs106,110,111 likely to increase quetiapine concentration.
Reports of these effects are conflicting112 and not sufficient to support the routine use
of plasma level monitoring based on these factors alone. Despite the substantial variation in plasma levels at each dose, there is insufficient evidence to suggest a target therapeutic range to aim for (although a target range of 100–500mcg/L has been proposed113),
thus plasma level monitoring is likely to have little value. Moreover, the metabolites of
quetiapine have major therapeutic effects and their concentrations are only loosely
associated with parent drug levels.114
Most current reports of quetiapine concentration associations are derived from the
analysis of trough samples. Because of the short half-­life of quetiapine, trough levels
tend to drop to within a relatively small range regardless of dose and previous peak
level. Peak plasma levels may be more closely related to dose and clinical response,105
although monitoring of such is not currently justified in the absence of an established
peak plasma target range. Interestingly, a study of quetiapine in patients with borderline personality disorder or drug-­induced psychosis showed a linear relationship
between response and 12-­hour plasma levels.112 Peak to trough variation is greater for
immediate-­release formulations (roughly a maximum of 4000mcg/L to zero) than for
slow-­release preparations (roughly a maximum of 3000mcg/L to around 100mcg/L).45

12 - Risperidone
Risperidone

13 - Target ranges for other psychotropics
Target ranges for other psychotropics
Pharmacokinetics
CHAPTER 11
Quetiapine has an established dose–response relationship, and appears to be well
tolerated at doses well beyond the licensed dose range.115 In practice, dose adjustment
should be based on patient response and tolerability.
Risperidone
The therapeutic range for risperidone is generally agreed to be 20–60mcg/L of the active
moiety (risperidone + 9-­OH-­risperidone)98,116,117 although other ranges (25–150mcg/L
and 25–80mcg/L) have been proposed.118 Plasma levels of 20–60mcg/L are usually
afforded by oral doses of between 3mg and 6mg a day.116,119–121 Occupancy of striatal
dopamine D2 receptors has been shown to be around 65% (the minimum required for
acute therapeutic effect) at plasma levels of approximately 20mcg/L.117,122
Limited data for paliperidone palmitate 1-­monthly long-­acting injection (LAI) suggest that standard loading doses give plasma levels of 25–45mcg/L; while at steady
state, plasma levels ranged from 10 to 25mcg/L for 100mg/month and 15 to 35mcg/L
for 150mg/month.123 Plasma concentrations may gradually rise in the first year of treatment to around 35mcg/L (mean dose 138mg/month)124 and remain stable thereafter.125
For the 3-­monthly injection, steady state plasma concentrations range from 30 to
55mcg/L for 525mg every 3 months, 25 to 55mcg/L for 350mg every 3 months and 20
to 35mcg/L for 263mg every 3 months.126,127 Six-­monthly paliperidone, available as 700
and 1000mg injections, provides similar plasma concentrations to those achieved by
the corresponding doses of 3-­monthly injections.128
Plasma concentrations of risperidone ISM® remain above 20mcg/L throughout the
dosing interval.129
Target ranges for other psychotropics
The target ranges listed in Table 11.2 have somewhat dubious usefulness and, in some
cases, merely represent the range of values seen in clinical use. Assays for these drugs
are likely to be available only in specialist units.
Table 11.2  Target ranges for other psychotropics.32,98,130
Target range (mcg/L)
Antipsychotics
Asenapine
1–5
Brexpiprazole
40–140
Cariprazine
10–20
Chlorpromazine
30–300
Flupentixol
0.5–5 (cis-­isomer)
Fluphenazine
1–10
Haloperidol
1–10
(Continued )
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Table 11.2  (Continued )
Iloperidone
5–10
Lurasidone
15–40
Melperone
30–100
CHAPTER 11
Sulpiride
200–1000
Ziprasidone
50–200
Zuclopenthixol
4–50
Antidepressants
Agomelatine
7–300
Citalopram
50–110
Desvenlafaxine
100–400
Dosulepin
45–100
Duloxetine
30–120
Escitalopram
15–80
Fluoxetine (+ norfluoxetine)
120–500
Fluvoxamine
60–230
Levomilnacipran
80–120
Mianserin
15–70
Milnacipram
100–150
Mirtazapine
30–80
Moclobemide
300–1000
Paroxetine
20–65
Reboxetine
60–350
Sertraline
10–150
Trazodone
700–1000
Venlafaxine
(+ O-­desmethylvenlafaxine)
100–400
Vilazodone
30–70
Vortioxetine
15–60
Target range (mcg/L)

14 - References
References
Pharmacokinetics
CHAPTER 11
References
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74. Khan AY, et al. Examining concentration-­dependent toxicity of clozapine: role of therapeutic drug monitoring. J Psychiatr Pract 2005;
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75. Varma S, et  al. Clozapine-­related EEG changes and seizures: dose and plasma-­level relationships. Ther Adv Psychopharmacol 2011;
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76. Greenwood-­Smith C, et al. Serum clozapine levels: a review of their clinical utility. J Psychopharmacol 2003; 17:234–238.
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15 - Interpreting postmortem blood concentrations
Interpreting postmortem blood concentrations
Pharmacokinetics
CHAPTER 11
Interpreting postmortem blood concentrations
Much is known about the distribution of drugs in the body during life but relatively
little about these same parameters after death. A great many drugs are subject to postmortem distribution changes but, for obvious practical reasons, research into the
mechanisms and extent of these effects is very limited. The best that can be said is that
a drug plasma concentration measured during life may be very different from the concentration measured at some time after death (usually in whole blood from the femoral artery).
A number of processes are responsible for these changes. In life, active mechanisms
serve to concentrate some drugs in certain organs or tissues. After death, passive diffusion occurs as cell membranes break down and this will mean that postmortem blood
samples will, for some drugs, show higher concentrations than were seen during life.
This is known as postmortem redistribution (PMR). In addition, central blood vessels
surrounding major organs often demonstrate much higher drug concentrations than
relatively distant peripheral samples.1 PMR and other processes are temperature-­ and
time-­dependent so time since death and conditions of storage are important determinants of blood concentration changes.2 PMR tends to be greater with drugs with a large
volume of distribution (i.e. those for which tissue concentrations in life vastly exceed
blood concentrations) especially when given over a long period during life.
Other processes of importance3 include the postmortem synthesis of certain compounds. For example, the body is able to generate gamma-­hydroxybutyrate. Trauma
may allow the introduction of yeasts that metabolise glucose to alcohol. Another phenomenon is the degradation of drugs by bacteria (e.g. clonazepam and nitrazepam) or
fungi. Also, the metabolism of some drugs (cocaine, for example) appears to continue
after death (although this may be simple chemical instability of the parent compound).
All of the processes described here contribute to an overall direction of change of
concentration postmortem. Antidepressant concentrations tend to increase in postmortem samples whereas those of benzodiazepines invariably decrease.4 Mirtazapine concentrations also appear to decrease.5,6 Antipsychotic concentrations both increase and
decrease depending on the drug.4 Thus, when an isolated postmortem concentration is
considered (i.e. one which cannot be compared with a concentration measured in life), it
can only be said that the in-­life concentration would have been higher or lower.7
Table  11.3 lists some of the factors relevant to drug concentration changes after
death and the possible consequences of these processes. Generally speaking, an isolated
postmortem blood concentration cannot be sensibly interpreted. Even where in-­life levels are available, for most drugs in most circumstances, interpretation of blood levels
after death is near impossible. High postmortem concentrations should certainly not be
taken, in the absence of other evidence, to indicate death by overdose, for example. Two
valuable reference sources for interpretation of postmortem sample analysis are the
systematic reviews of Ketola and Kriikku8 and Ketola and Ojanperä.9 Expert advice
should always be sought when considering the role of medication in a death.10

16 - References
References
880
The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 11
References
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Maskell PD. Just say no to postmortem drug dose calculations. J Forensic Sci 2021; 66:1862–1870.
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Ketola RA, et al. Summary statistics for drug concentrations in post-­mortem femoral blood representing all causes of death. Drug Test Anal
2019; 11:1326–1337.
Flanagan RJ. Poisoning: fact or fiction? Med Leg J 2012; 80:127–148.
Flanagan RJ, et al. Effect of post-­mortem changes on peripheral and central whole blood and tissue clozapine and norclozapine concentrations in the domestic pig (Sus scrofa). Forensic Sci Int 2003; 132:9–17.
Flanagan RJ, et al. Suspected clozapine poisoning in the UK/Eire, 1992–2003. Forensic Sci Int 2005; 155:91–99.
Saar E, et al. The time-­dependant post-­mortem redistribution of antipsychotic drugs. Forensic Sci Int 2012; 222:223–227.
Caplehorn JR, et al. Methadone dose and post-­mortem blood concentration. Drug Alcohol Rev 2002; 21:329–333.
Lewis RJ, et al. Paroxetine in postmortem fluids and tissues from nine aviation accident victims. J Anal Toxicol 2015; 39:637–641.
Launiainen T, et al. Drug concentrations in post-­mortem femoral blood compared with therapeutic concentrations in plasma. Drug Test Anal
2014; 6:308–316.
Soderberg C, et al. Reference values of lithium in postmortem femoral blood. Forensic Sci Int 2017; 277:207–214.
Linnet K, et al. Postmortem femoral blood concentrations of risperidone. J Anal Toxicol 2014; 38:57–60.
Skov L, et al. Postmortem femoral blood reference concentrations of aripiprazole, chlorprothixene, and quetiapine. J Anal Toxicol 2015;
39:41–44.
Rodda KE, et al. The redistribution of selected psychiatric drugs in post-­mortem cases. Forensic Sci Int 2006; 164:235–239.
Scanlon KA, et al. Comprehensive duloxetine analysis in a fatal overdose. J Anal Toxicol 2016; 40:167–170.
Breivik H, et al. Post mortem tissue distribution of quetiapine in forensic autopsies. Forensic Sci Int 2020; 315:110413.
Butzbach DM, et al. Bacterial degradation of risperidone and paliperidone in decomposing blood. J Forensic Sci 2013; 58:90–100.
Martinez-­Ramirez JA, et al. Search for fungi-­specific metabolites of four model drugs in postmortem blood as potential indicators of
postmortem fungal metabolism. Forensic Sci Int 2016; 262:173–178.
Martinez-­Ramirez JA, et al. Studies on drug metabolism by fungi colonizing decomposing human cadavers. Part II: biotransformation of five
model drugs by fungi isolated from post-­mortem material. Drug Test Anal 2015; 7:265–279.
Table 11.3  Factors affecting postmortem blood concentrations.
Factor
Examples
Consequences
Redistribution of drug from
tissues to blood compartment
Most drugs with large volume of distribution,
e.g. clozapine,11,12 olanzapine,13 methadone,14
SSRIs,15 TCAs, mirtazapine,16 lithium17
May not occur to any significant effect with
risperidone,4,18 aripiprazole19 or quetiapine4,19
Postmortem levels up to
10× higher than in-­life levels,
sometimes higher still9
Uneven distribution of drugs in
the blood compartment and in
organs (i.e. site of blood
collection affects concentration)
Most drugs,8,20 e.g. clozapine, TCAs, SSRIs,
duloxetine,21 benzodiazepines, quetiapine22
Concentrations may vary
several-­fold according to site of
collection at postmortem, e.g.
femoral blood vs heart blood
Decay of drugs in postmortem
tissue (usually by bacterial
degradation)
Not widely studied but known to occur with
olanzapine, risperidone23 and some
benzodiazepines. Fungi can metabolise
amitriptyline, mirtazapine and zolpidem.24,25
Postmortem levels may be
lower than in-­life levels
Postmortem metabolism/
degradation
Cocaine metabolised/degraded postmortem.
Many other drugs are unstable in
postmortem samples. Yeasts may produce
ethanol following trauma.3
Postmortem levels may be
lower (cocaine) or higher
(alcohol) than in-­life levels
TCAs, tricyclic antidepressants.

17 - Acting on clozapine plasma concentration resu
Acting on clozapine plasma concentration results
Pharmacokinetics
CHAPTER 11
Acting on clozapine plasma concentration results
In most developed countries, clozapine blood concentration monitoring is widely
used. Table 11.4 gives some general advice about actions that should be taken when
clozapine levels are within a certain range. The ranges shown are somewhat arbitrary
and convenient – the concentration at which a particular patient might respond cannot be known without a trial of clozapine. Most adverse effects are linearly or exponentially related to dose or plasma level. That is, there is no step-­change in the risk of
seizures, for example, at a particular dose or plasma concentration.1 The same is
broadly true of therapeutic effects. The likelihood of response in an individual increases
from concentrations below the accepted therapeutic range up to around 1000mcg/L.2–4
Table 11.4 should be considered more an aid to decision-­making rather than a rigorous, unbending evidence-­based instruction. Note also the effect of tolerance to adverse
effects – many patients have a significant adverse effect burden before therapeutic
concentrations are reached,5 reducing over time as tolerance develops.
Table 11.4  Recommended actions in response to clozapine concentrations.*
Plasma
concentration
Response
status
Tolerability
status
Suggested action
<350mcg/L
Poor
Poor
Increase dose very slowly to give level of 350mcg/L
Poor
Good
Increase dose to give level of 350mcg/L
Good
Poor
Maintain dose. Consider cautious dose reduction if
tolerability does not improve.
Good
Good
Continue to monitor. No action required.
350–500mcg/L
Poor
Poor
Increase dose slowly, according to tolerability, to give level
of >500mcg/L. Consider prophylactic anticonvulsant.† If no
improvement, consider augmentation.
Poor
Good
Increase dose slowly, according to tolerability, to give level
of >500mcg/L (up to 1000mcg/mL if tolerated). Consider
prophylactic anticonvulsant.† If no improvement, consider
augmentation.
Good
Poor
Maintain dose to see if tolerability improves. Consider
cautious dose reduction to give plasma level of around
350mcg/L.
Good
Good
Continue to monitor. No action required.
500–1000mcg/L
Poor
Poor
Consider use of prophylactic antiseizure drug.† Consider
augmentation. Attempt dose reduction if augmentation
successful.
Poor
Good
Consider use of prophylactic antiseizure drug.† Slowly
increase dose (up towards 1000mcg/mL if tolerated). Also
consider augmentation.
Good
Poor
Attempt slow dose reduction to give plasma level of
350–500mcg/L unless there is known non-­response at lower
level. If this is the case, maintain dose and consider adding
anticonvulsant.† Optimise treatment of adverse effects.
Good
Good
Consider use of prophylactic antiseizure drug.† Maintain
dose if good tolerability continues.
(Continued )

18 - References
References
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The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 11
References
Varma S, et  al. Clozapine-­related EEG changes and seizures: dose and plasma-­level relationships. Ther Adv Psychopharmacol 2011;
1:47–66.
Northwood K, et al. Optimising plasma clozapine levels to improve treatment response: an individual patient data meta-­analysis and receiver
operating characteristic curve analysis. Br J Psychiatry 2023; 222:241–245.
Tralongo F, et al. Association between clozapine plasma concentrations and treatment response: a systematic review, meta-­analysis and
individual participant data meta-­analysis. Clin Pharmacokinet 2023; 62:807–818.
Bogers J, et al. Feasibility and effect of increasing clozapine plasma levels in long-­stay patients with treatment-­resistant schizophrenia. J Clin
Psychopharmacol 2023; 43:97–105.
Yusufi B, et al. Prevalence and nature of side effects during clozapine maintenance treatment and the relationship with clozapine dose and
plasma concentration. Int Clin Psychopharmacol 2007; 22:238–243.
Malik S, et  al. Sodium valproate and clozapine induced neutropenia: a case control study using register data. Schizophr Res 2018;
195:267–273.
Table 11.4  (Continued )
Plasma
concentration
Response
status
Tolerability
status
Suggested action
1000mcg/L
Poor
Poor
Add antiseizure drug. Attempt augmentation. Reduce dose
to give level of <1000mcg/L. Consider abandoning
clozapine treatment.
Poor
Good
Add antiseizure drug. Attempt augmentation. If
augmentation successful, reduce dose to give level
<1000mcg/L. If unsuccessful, consider abandoning
clozapine treatment.
Good
Poor
Add antiseizure drug. Attempt slow dose reduction to give
plasma level <1000mcg/L.
Good
Good
Add antiseizure drug. Monitor closely; attempt dose
reduction only if tolerability declines.
Notes
Poor response
No response or unsatisfactory response to clozapine. For example, not sufficiently well to
be discharged.
Good response
Obvious positive changes related to use of clozapine. Patient likely to be suitable for
discharge to either supported or unsupported care in the community.
Poor tolerability
Dose constrained by adverse effects such as tachycardia, sedation, hypersalivation,
hypotension, etc. (see Chapter 1 for suggestions of treatment for adverse effects).
Good tolerability
Patient tolerates treatment well and there are no signs of serious toxicity.
Augmentation
Adding another antipsychotic or mood stabiliser (see Chapter 1).
In all situations, ensure adequate treatment for clozapine-­induced constipation. Constipation is dose-­related. Ensure
regular bowel movements and record bowel function. Stimulant laxatives such as senna are required (see Chapter 1).
Seizures are dose-­ and plasma level-­dependent. Suitable antiseizure agents are valproate, lamotrigine and, rarely,
topiramate. Use lamotrigine if response is poor; valproate if affective symptoms are present (see Chapter 2). Note that
use of valproate increases risk of neutropenia with clozapine.6 Both valproate and topiramate are contraindicated in
women of child-­bearing age.
*This table applies to results for patients on a stable clozapine dose with confirmed good adherence.
†Antiseizure drugs should usually be used in patients whose plasma level exceeds 600mcg/L, unless EEG is normal, and
in those with lower plasma levels who experience clozapine-­induced seizures.

19 - Psychotropic drugs and cytochrome (CYP) funct
Psychotropic drugs and cytochrome (CYP) function
Pharmacokinetics
CHAPTER 11
Psychotropic drugs and cytochrome (CYP) function
Information on the effect of drugs on CYP function helps predict or confirm
­suspected interactions that may not have been uncovered in regulatory trials or in
clinical use.
In addition to the effect of co-­administered drugs on CYP function, genetic polymorphism associated with some enzymes may also account for inter-­individual variations
in the metabolism of certain drugs. Genetic variation influences both likelihood of
response and tolerability (see later in this section for more information on genetic
variation).1,2
The effects of polymorphism and pharmacokinetic interaction are difficult to
predict because some drugs are metabolised by more than one enzyme and an
alternative pathway(s) may compensate if other enzyme pathways are inhibited. A
further complication is that CYPs are active in sites other than the liver (e.g. gut,
brain). The effect of psychotropics on brain CYPs can be markedly different from
hepatic CYPs.3
The function of CYPs is not the only consideration. P-­glycoprotein (P-­gp) is a drug
transporter protein found in the gut wall. P-­gp can eject (active process) drugs that diffuse (passive process) across the gut wall. P-­gp is also found in testes and in the blood–
brain barrier. Drugs that inhibit P-­gp are anticipated to increase the uptake of other
drugs (that are substrates for P-­gp), and drugs that induce P-­gp are anticipated to reduce
the uptake of other drugs (that are substrates for P-­gp). Many drugs that are substrates
for CYP3A4 have also been found to be substrates for P-­gp.
Uridine diphosphate (UDP)-­glucuronosyltransferase (UGT) has been identified as an
enzyme that is responsible for phase II (conjugation) reactions. Valproate is a potent
inhibitor of UGT, hence its interaction with lamotrigine, a drug which is primarily
metabolised by UGT. UGT enzymes are also involved in the metabolism of lumateperone, olanzapine, topiramate and trifluoperazine.
In Table 11.5, drugs highlighted in bold indicate:
■
■Predominant metabolic enzyme pathway, or
■
■Predominant enzyme activity (inhibition or induction).
Drugs annotated with * are known to be a minor metabolic enzyme pathway or
activity (i.e. not demonstrated to be clinically significant). Drugs in normal font (not
bold and without *) indicate metabolic enzyme pathway(s) or activity where significance is unclear or unknown.
Table 11.5 does not include details of the effects of non-­psychotropics on CYP
function.
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The Maudsley® Prescribing Guidelines in Psychiatry
Table 11.5  Effects of psychotropics on CYP function.
CYP1A2
Substrates
Inhibitors
Inducers
Asenapine4
Agomelatine
Amitriptyline*
Bupropion*
Caffeine
Chlorpromazine
Clomipramine*
Clozapine
Duloxetine
Fluphenazine
Fluvoxamine
Haloperidol
Imipramine*
Levomepromazine
Lumateperone
Melatonin
Mirtazapine*
Olanzapine
Perphenazine
Pimozide*
Ramelteon
Zolpidem*
CHAPTER 11
Moclobemide
Perphenazine
CYP2A6
Substrates
Inhibitors
Inducers
Bupropion*
Caffeine
Nicotine
CYP2B6
Substrates
Inhibitors
Inducers
Bupropion
Methadone*
Nicotine
Sertraline*
Fluoxetine*
Fluvoxamine
Memantine
Paroxetine*
Sertraline*
CYP2B7
Substrates
Inhibitors
Inducers
Buprenorphine*
Not known
Not known
‘Barbiturates’
Carbamazepine
Modafinil*
Phenobarbital
Phenytoin
Fluvoxamine
Iloperidone
Levomepromazine
Melatonin5
Tranylcypromine
Phenobarbital
Carbamazepine*
Modafinil*
Phenobarbital
Phenytoin
Table 11.5  (Continued )
CYP2C8
Substrates
Inhibitors
Inducers
Lumateperone
Zopiclone*
Not known
Not known
CYP2C9
Substrates
Inhibitors
Inducers
Fluoxetine*
Fluvoxamine
Modafinil
Valproate
Agomelatine*
Amitriptyline
Bupropion*
Doxepin
Fluoxetine*
Lamotrigine
Phenobarbital
Phenytoin
Sertraline*
Valproate
CYP2C19
Substrates
Inhibitors
Inducers
Escitalopram*
Fluoxetine
Fluvoxamine
Iloperidone
Melatonin5
Agomelatine*
Amitriptyline
Atomoxetine
Carbamazepine*
Citalopram
Clomipramine*
Diazepam
Escitalopram
Fluoxetine*
Imipramine*
Melatonin
Methadone
Moclobemide
Phenytoin
Sertraline*
Suvorexant
Trimipramine*
Valproate
Moclobemide
Modafinil
Topiramate
Pharmacokinetics
CHAPTER 11
Carbamazepine
SJW
Carbamazepine
SJW
(Continued )
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The Maudsley® Prescribing Guidelines in Psychiatry
Table 11.5  (Continued )
CYP2D6
Substrates
Inhibitors
Inducers
‘Amfetamines’
Amitriptyline
Aripiprazole
Atomoxetine
CHAPTER 11
Brexpiprazole
Cariprazine
Chlorpromazine
Citalopram
Clomipramine
Clozapine*
Deutetrabenazine
Donepezil*
Doxepin
Duloxetine
Escitalopram
Fluoxetine
Fluphenazine
Fluvoxamine
Galantamine
Haloperidol
Iloperidone
Imipramine
Methadone*
Mianserin
Mirtazapine*
Moclobemide
Nortriptyline
Olanzapine
Paroxetine
Perphenazine
Pimavanserin
Pimozide*
Quetiapine*
Risperidone
Sertindole
Sertraline
Trazodone*
Trimipramine
Valbenazine
Venlafaxine
Vortioxetine
Zuclopenthixol
CYP2E1
Substrates
Inhibitors
Inducers
Bupropion
Ethanol
Disulfiram
Paracetamol
Ethanol
Amitriptyline
Asenapine4
Not known
Bupropion
Chlorpromazine
Citalopram*
Clomipramine
Clozapine
Doxepin
Duloxetine
Escitalopram
Fluoxetine
Fluphenazine
Fluvoxamine*
Haloperidol
Iloperidone
Levomepromazine
Methadone*
Moclobemide
Paroxetine
Perphenazine
Reboxetine*
Risperidone
Sertraline*
Venlafaxine*
Ziprasidone*
Table 11.5  (Continued )
CYP3A4
Substrates
Inhibitors
Inducers
Alfentanyl
Alprazolam
Amitriptyline
Aripiprazole
Atomoxetine*
Fluoxetine
Fluvoxamine
Iloperidone
Blonaserin
Brexipiprazole
Buprenorphine
Bupropion*
Buspirone
Carbamazepine
Cariprazine
Chlorpromazine
Citalopram
Clomipramine*
Clonazepam
Clozapine*
Diazepam
Donepezil
Dosulepin
Escitalopram*
Fentanyl
Fluoxetine*
?Flurazepam
Galantamine
Haloperidol
Imipramine
Lemborexant
Levomepromazine
Lumateperone
Lurasidone
Methadone
Midazolam
Mirtazapine
Modafinil
Nitrazepam
Paliperidone
Perphenazine
Pimavanserin
Pimozide
Quetiapine
Reboxetine
Risperidone*
Sertindole
Sertraline*
Suvorexant
Trazodone
Trimipramine*
Valbenazine
Venlafaxine
Vilazodone
Zaleplon
Ziprasidone
Zolpidem
Zopiclone
Zuclopenthixol
Levomepromazine
Paroxetine
Perphenazine
Reboxetine*
Ziprasidone*
Note: information on CYP function is derived from individual SPCs and US labelling
(accessed August 2024), from systematic reviews7,8 and the Flockhart table.9
SJW, St John’s wort; SPC, summary of product characteristics.
Asenapine?
Carbamazepine
Clozapine6
Levomepromazine6
Modafinil
Phenobarbital
‘and probably
other barbituates’
Phenytoin
SJW
Topiramate
CHAPTER 11

20 - Genetics of cytochrome function
Genetics of cytochrome function
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The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 11
Genetics of cytochrome function
The function of CYPs is under genetic control. Each individual’s CYP function is
determined by heredity and is often, but not always, linked to ethnicity. Phenotypes are
usually described as poor metabolisers, intermediate metabolisers, normal metabolisers
and rapid or ultrarapid metabolisers. Table 11.6 gives the approximate distribution of
phenotypes across nine ethnicities. Awareness of differences in phenotype frequencies
can help predict and understand drug metabolism differences. As an example, CYP1A2
ultrarapid metaboliser phenotypes are most often seen in African Americans and so we
might expect a higher rate of clozapine failure (or at least low plasma levels) in this
population.
Table 11.6  Estimated phenotype frequency by ancestry for CYP1A2, CYP2D6, CYP2C19, CYP2C9 and CYP3A4.10–22
Genotype-­predicted
phenotypes
African10,11
African American12,13
European ancestry +
North American14
Near Eastern
East Asian
South/Central Asian
Americas
Latino15
Oceanian
CYP1A2
Ultrarapid metaboliser
10–20%
15–30%
1–4%
5–10%
1–5%
3–8%
5–10%
7–12%
5–10%
Normal metaboliser
55–70%
50–60%
70–80%
65–75%
65–75%
60–70%
60–70%
65–75%
65–75%
Intermediate metaboliser
10–20%
10–15%
10–15%
10–15%
10–20%
10–15%
10–15%
10–15%
10–15%
Poor metaboliser
5–10%
5–10%
5–10%
5–10%
10–15%
10–15%
5–10%
5–10%
5–10%
CYP2D6
Ultrarapid metaboliser
4%
5%
3%
10%
1%
2%
6%
4%
20%
Normal metaboliser
43%
56%
51%
55%
52%
62%
64%
59%
67%
Intermediate metaboliser
44%
36%
39%
30%
39%
30%
24%
29%
10%
Poor metaboliser
2%
2%
7%
2%
1%
2%
2%
3%
0%
CYP2C19
Ultrarapid metaboliser
3%
4%
5%
4%
0%
3%
1%
3%
0%
Rapid metaboliser
19%
24%
27%
26%
3%
19%
14%
24%
2%
Normal metaboliser
30%
33%
40%
45%
38%
30%
63%
53%
4%
Intermediate metaboliser
36%
31%
26%
24%
46%
41%
21%
19%
37%
Likely intermediate
metaboliser
4%
3%
0%
0%
0%
0%
0%
0%
0%
Poor metaboliser
6%
4%
2%
2%
13%
8%
2%
1%
57%
Likely poor metaboliser
1%
1%
0%
0%
0%
0%
0%
0%
0%
CYP2C9
Normal metaboliser
73%
76%
63%
61%
84%
60%
83%
75%
91%
(Continued )
Table 11.6  (Continued )
Genotype-­predicted
phenotypes
African10,11
African American12,13
European ancestry +
North American14
Near Eastern
East Asian
South/Central Asian
Americas
Latino15
Oceanian
Intermediate metaboliser
26%
24%
35%
36%
15%
36%
16%
25%
9%
Poor metaboliser
1%
1%
3%
3%
1%
4%
0%
1%
0%
CYP3A4
Ultrarapid metaboliser
7–15%
10–15%
1–5%
5–10%
1–4%
2–6%
4–9%
3–8%
4–10%
Normal metaboliser
50–65%
55–70%
65–75%
60–70%
60–75%
60–70%
55–65%
60–70%
60–70%
Intermediate metaboliser
15–25%
10–20%
15–20%
15–20%
15–25%
15–20%
15–20%
15–20%
15–20%
Poor metaboliser
5–10%
5–10%
5–10%
5–10%
5–10%
5–10%
5–10%
5–10%
5–10%

21 - References
References
Pharmacokinetics
CHAPTER 11
References
Baldacci A, et al. Pharmacogenetic guidelines for psychotropic drugs: optimizing prescriptions in clinical practice. Pharmaceutics 2023;
15:2540.
Cojocaru A, et al. The implications of cytochrome P450 2D6/CYP2D6 polymorphism in the therapeutic response of atypical antipsychotics
in adolescents with psychosis – a prospective study. Biomedicines 2024; 12:494.
Daniel WA, et al. The mechanisms of interactions of psychotropic drugs with liver and brain cytochrome P450 and their significance for drug
effect and drug-­drug interactions. Biochem Pharmacol 2022; 199:115006.
Wójcikowski J, et al. In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction
of possible drug-­drug interactions. Pharmacol Rep 2020; 72:612–621.
Matura JM, et al. Dietary supplements, cytochrome metabolism, and pharmacogenetic considerations. Ir J Med Sci 2022; 191:2357–2365.
Danek PJ, et al. Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4. Pharmacol
Rep 2021; 73:303–308.
Hart XM, et al. Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: focus on antipsychotics. World J Biol Psychiatry 2024:1–123.
Schoretsanitis G, et al. TDM in psychiatry and neurology: a comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians. World J Biol Psychiatry 2018; 19:162–174.
Indiana University School of Medicine. Drug Interactions Flockhart Table™ 2024 (last accessed August 2024); https://drug-­interactions.
medicine.iu.edu/MainTable.aspx.
Masimirembwa CM, et al. Genetic polymorphism of drug metabolising enzymes in African populations: implications for the use of neuroleptics and antidepressants. Brain Res Bull 1997; 44:561–571.
Aklillu E, et al. Genetic polymorphism of CYP1A2 in Ethiopians affecting induction and expression: characterization of novel haplotypes
with single-­nucleotide polymorphisms in intron 1. Mol Pharmacol 2003; 64:659.
Muscat JE, et  al. Comparison of CYP1A2 and NAT2 phenotypes between black and white smokers. Biochem Pharmacol 2008;
76:929–937.
Wrighton SA, et al. The human hepatic cytochromes P450 involved in drug metabolism. Crit Rev Toxicol 1992; 22:1–21.
Rasmussen BB, et al. The interindividual differences in the 3-­demthylation of caffeine alias CYP1A2 is determined by both genetic and environmental factors. Pharmacogenetics 2002; 12:473–478.
Ingelman-­Sundberg M, et al. Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and
clinical aspects. Pharmacol Ther 2007; 116:496–526.
Stanford University. PharmGKB. 2024 (last accessed August 2024); https://www.pharmgkb.org.
Zhou SF, et al. Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome
P450 1A2. AAPS J 2009; 11:481–494.
Myriad Genetics. Genesight. 2024 (last accessed August 2024); https://www.genesight.com.
Enoch MA, et al. Using ancestry-­informative markers to define populations and detect population stratification. J Psychopharmacol 2006;
20:19–26.
Genetic Lifehacks. 2024 (last accessed August 2024); https://www.geneticlifehacks.com.
Guttman Y, et al. Polymorphism in cytochrome P450 3A4 is ethnicity related. Front Genet 2019; 10:224.
Darney K, et al. Inter-­ethnic differences in CYP3A4 metabolism: a Bayesian meta-­analysis for the refinement of uncertainty factors in chemical
risk assessment. Computational Toxicol 2019; 12:100092.

22 - Smoking and psychotropic drugs
Smoking and psychotropic drugs
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The Maudsley® Prescribing Guidelines in Psychiatry
CHAPTER 11
Smoking and psychotropic drugs
Tobacco smoke contains polycyclic aromatic hydrocarbons that induce certain hepatic
enzymes (CYP1A2 in particular).1 Other enzymes that may be induced by smoking
are CYP2C19 and, possibly, CYP3A4 and some variants of UGT (glycosyltransferases).2 The extent of enzyme induction is determined by the number and type of
cigarettes smoked and by the degree of smoke inhalation.3 For some drugs used in
psychiatry, smoking significantly reduces drug plasma levels and higher doses are
required than in non-­smokers. Smoking may also affect alcohol metabolism by inducing CYP2E1.3
When people stop smoking, enzyme activity halves roughly every 2 days.4 It is very
important to appreciate that nicotine replacement and vaping have no effect on this
process (they do not contain polycyclic aromatic hydrocarbons). Plasma levels of
affected drugs will then rise, sometimes substantially. Dose reduction will usually be
necessary. If smoking is restarted, enzyme activity increases, plasma levels fall and dose
increases are then required. The process is complicated, and effects are difficult to predict. Of course, few people manage to give up smoking completely, so additional complexity is introduced by intermittent smoking and repeated attempts at stopping
completely. Close monitoring of plasma levels (where useful), clinical progress and
adverse effect severity are essential.
Table  11.7 gives details of psychotropic drugs known to be affected by smoking
status.
Table 11.7  Effect of smoking on psychotropic drugs.
Drug
Effect of smoking
Action to be taken on
stopping smoking
Action to be taken on
restarting smoking
Agomelatine5
Plasma levels reduced
Monitor closely. Dose may
need to be reduced.
Consider reintroducing
previous smoking dose.
Benzodiazepines3,6
Plasma levels reduced by
0–50% (depends on drug and
smoking status)
Monitor closely. Consider
reducing dose by up to 25%
over 1 week.
Monitor closely.
Consider restarting
‘normal’ smoking dose.
Carbamazepine3
Unclear, but smoking may
reduce carbamazepine plasma
levels to a small extent.
Monitor for changes in
severity of adverse effects.
Monitor plasma levels.
Chlorpromazine3,6,7
Plasma levels reduced. Varied
estimates of exact effect.
Monitor closely. Consider
dose reduction.
Monitor closely.
Consider restarting
previous smoking dose.
Clozapine8–10
Reduces plasma levels by up to
50%. Effect may be maximal
at as few as 2–5 cigarettes a
day.11 Plasma level reduction
and risk of relapse may be
greater in those receiving
valproate.12 Effect is reversed
by co-­administered
fluvoxamine.13
Take plasma level before
stopping. On stopping,
reduce dose gradually (over
a week) until around 75%
of original dose is reached
(i.e. reduce by 25%). Repeat
plasma level 1 week after
stopping. Anticipate further
dose reductions.
Take plasma level before
restarting. Increase dose
to previous smoking
dose over 1 week.
Repeat plasma level.
Deterioration is
common if dose
increases allow a fall in
blood levels.14
Duloxetine15,16
Plasma levels may be reduced
by up to 50%.
Monitor closely. Dose may
need to be reduced.
Consider reintroducing
previous smoking dose.
Pharmacokinetics
CHAPTER 11
Table 11.7  (Continued )
Drug
Effect of smoking
Action to be taken on
stopping smoking
Action to be taken on
restarting smoking
Escitalopram17
In practice, smokers have
lower blood levels despite
being given higher doses.
Reduction in levels may be up
to 50% (possibly via induction
of CYP2C19).
Monitor closely. Consider
25% dose reduction.
Monitor closely.
Reinstate smoking dose.
Fluphenazine18
Reduces plasma levels by up to
50%
On stopping, reduce dose by
25%. Monitor carefully over
following 4–8 weeks.
Consider further dose
reductions.
On restarting, increase
dose to previous
smoking dose.
Fluvoxamine19
Plasma levels decreased by
around a third
Monitor closely. Dose may
need to be reduced.
Dose may need to be
increased to previous
level.
Haloperidol20,21
Reduces plasma levels by
around 25–50%
Reduce dose by around
25%. Monitor carefully.
Consider further dose
reductions.
On restarting, increase
dose to previous
smoking dose.
Loxapine22 (inhaled)
Half-­life reduced from 15.7 to
13.6 hours
Monitor
Monitor
Mirtazapine23
Unclear, but effect probably
minimal
Monitor
Monitor
Olanzapine10,24–26
Reduces plasma levels by up to
50%. Effect increases with
number of cigarettes
smoked.26
Take plasma level before
stopping. On stopping,
reduce dose by 25%. After
1 week, repeat plasma level.
Consider further dose
reductions.
Take plasma level before
restarting. Increase dose
to previous smoking
dose over 1 week.
Repeat plasma level.
Risperidone2,27
Active moiety concentrations
probably lower in smokers.
Minor effect (possibly via
induction of CYP3A4).
Smoking may not affect
paliperidone concentrations.28
Monitor closely
Monitor closely
Trazodone29
Around 25% reduction
Monitor for increased
sedation. Consider dose
reduction.
Monitor closely.
Consider increasing
dose.
Tricyclic
antidepressants3,6,30
Plasma levels reduced by
25–50%. Some studies
suggest more limited effect.2,31
Monitor closely. Consider
reducing dose by 10–25%
over 1 week. Consider
further dose reductions.
Monitor closely.
Consider restarting
previous smoking dose.
Zuclopenthixol32,33
Unclear, but effect probably
minimal
Monitor
Monitor
Note (again: it bears repeating): only tobacco smoking induces hepatic enzymes in the manner described above. This
includes cigarettes and cannabis/tobacco ‘joints’. Nicotine replacement, vaping devices and electronic cigarettes
(which do not contain polycyclic aromatic compounds) have no effect on enzyme activity.34,35

23 - References
References
894
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CHAPTER 11
References
Kroon LA. Drug interactions with smoking. Am J Health Syst Pharm 2007; 64:1917–1921.
Scherf-­Clavel M, et al. Analysis of smoking behavior on the pharmacokinetics of antidepressants and antipsychotics: evidence for the role of
alternative pathways apart from CYP1A2. Int Clin Psychopharmacol 2019; 34:93–100.
Desai HD, et al. Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective. CNS Drugs 2001; 15:469–494.
Faber MS, et al. Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clin Pharmacol Ther 2004; 76:178–184.
Servier Laboratories Limited. Summary of product characteristics. Valdoxan (agomelatine). 2021; https://www.medicines.org.uk/emc/
medicine/21830.
Miller LG. Recent developments in the study of the effects of cigarette smoking on clinical pharmacokinetics and clinical pharmacodynamics.
Clin Pharmacokinet 1989; 17:90–108.
Goff DC, et al. Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 1992;
149:1189–1194.
Haring C, et al. Influence of patient-­related variables on clozapine plasma levels. Am J Psychiatry 1990; 147:1471–1475.
Diaz FJ, et al. Estimating the size of the effects of co-­medications on plasma clozapine concentrations using a model that controls for clozapine
doses and confounding variables. Pharmacopsychiatry 2008; 41:81–91.
Tsuda Y, et al. Meta-­analysis: the effects of smoking on the disposition of two commonly used antipsychotic agents, olanzapine and clozapine.
BMJ Open 2014; 4:e004216.
Flanagan RJ, et al. Effect of cigarette smoking on clozapine dose and on plasma clozapine and N-­desmethylclozapine (norclozapine) concentrations in clinical practice. J Clin Psychopharmacol 2023; 43:514–519.
Tsukahara M, et al. Effect of smoking habits and concomitant valproic acid use on relapse in patients with treatment-­resistant schizophrenia
receiving clozapine: a 1-­year retrospective cohort study. Acta Psychiatr Scand 2023; 148:437–446.
Augustin M, et  al. Effect of fluvoxamine augmentation and smoking on clozapine serum concentrations. Schizophr Res 2019;
210:143–148.
Qurashi I, et al. Changes in smoking status, mental state and plasma clozapine concentration: retrospective cohort evaluation. BJPsych Bull
2019; 43:271–274.
Fric M, et al. The influence of smoking on the serum level of duloxetine. Pharmacopsychiatry 2008; 41:151–155.
Augustin M, et al. Differences in duloxetine dosing strategies in smoking and nonsmoking patients: therapeutic drug monitoring uncovers the
impact on drug metabolism. J Clin Psychiatry 2018; 79:17m12086.
Scherf-­Clavel M, et al. Smoking is associated with lower dose-­corrected serum concentrations of escitalopram. J Clin Psychopharmacol 2019;
39:485–488.
Ereshefsky L, et al. Effects of smoking on fluphenazine clearance in psychiatric inpatients. Biol Psychiatry 1985; 20:329–332.
Spigset O, et al. Effect of cigarette smoking on fluvoxamine pharmacokinetics in humans. Clin Pharmacol Ther 1995; 58:399–403.
Jann MW, et  al. Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance.
Psychopharmacology (Berl) 1986; 90:468–470.
Shimoda K, et al. Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. Ther Drug Monit 1999;
21:293–296.
Takahashi LH, et al. Effect of smoking on the pharmacokinetics of inhaled loxapine. Ther Drug Monit 2014; 36:618–623.
Grasmader K, et al. Population pharmacokinetic analysis of mirtazapine. Eur J Clin Pharmacol 2004; 60:473–480.
Carrillo JA, et al. Role of the smoking-­induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-­state concentration of
olanzapine. J Clin Psychopharmacol 2003; 23:119–127.
Lowe EJ, et  al. Impact of tobacco smoking cessation on stable clozapine or olanzapine treatment. Ann Pharmacother 2010;
44:727–732.
Horvat M, et al. Association of smoking cigarettes, age, and sex with serum concentrations of olanzapine in patients with schizophrenia.
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Schoretsanitis G, et al. Effect of smoking on risperidone pharmacokinetics – a multifactorial approach to better predict the influence on drug
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Schoretsanitis G, et al. Lack of smoking effects on pharmacokinetics of oral paliperidone—­analysis of a naturalistic therapeutic drug monitoring sample. Pharmacopsychiatry 2021; 54:31–35.
Ishida M, et al. Effects of various factors on steady state plasma concentrations of trazodone and its active metabolite m-­chlorophenylpiperazine.
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Ereshefsky L, et al. Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine – new data and review. Clin Chem 1988; 34:863–880.
Lundstrøm NH, et al. The effect of smoking on the plasma concentration of tricyclic antidepressants: a systematic review. Acta Neuropsychiatr
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Jorgensen A, et  al. Zuclopenthixol decanoate in schizophrenia: serum levels and clinical state. Psychopharmacology (Berl) 1985;
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and clinical effect. Ment Health Clin 2021; 11:365–368.

24 - Drug interactions with alcohol
Drug interactions with alcohol

25 - Pharmacokinetic interactions14
Pharmacokinetic interactions1–4
Pharmacokinetics
CHAPTER 11
Drug interactions with alcohol
Drug interactions with alcohol are complex. Many patient-­related and drug-­related
factors need to be considered. It can be difficult to predict outcomes accurately because
a number of processes may occur simultaneously or consecutively.
Pharmacokinetic interactions1–4
Alcohol (ethanol) is absorbed from the gastrointestinal tract and distributed in body
water. The volume of distribution is smaller in women and the elderly where plasma
levels of alcohol will be higher than in young males for a given intake of alcohol.
Ingested alcohol is subject to metabolism by alcohol dehydrogenase (ADH). A small
proportion of alcohol is metabolised by ADH in the stomach. The remainder is metabolised in the liver by ADH, and by CYP2E1. At low alcohol concentrations only ADH is
active; CYP2E1 only begins to contribute when concentrations approach the legal driving limit of many countries (0.08%).5 CYP2E1 plays a minor role in occasional drinkers but is an important and inducible metabolic route in chronic, heavy drinkers. The
induction of CYP2E1 accounts for the apparent tolerance of alcohol in heavy drinkers.6
CYP1A2, CYP3A4 and many other CYP enzymes also play a minor role in the metabolism of ethanol.7,8
CYP2E1 and ADH convert alcohol to acetaldehyde. This is both the toxic substance
responsible for the unpleasant symptoms of the ‘Antabuse reaction’ (e.g. flushing, headache, nausea, malaise) and the compound implicated in hepatic damage. It may have
psychotropic effects – ethanol is metabolised to acetaldehyde by CYP2E1 in the brain.9
The enzyme catalase is also known to metabolise alcohol to acetaldehyde in the brain
and elsewhere.10 Acetaldehyde is further metabolised by aldehyde dehydrogenase to
acetic acid and then to carbon dioxide and water (Figure 11.1).
This is a minor route in occasional drinkers, and a major route in heavy drinkers and at higher blood
alcohol concentration. The ubiquitous enzyme catalase is also able to metabolise ethanol but its overall
contribution is not known.
Alcohol
dehydrogenase
(ADH)
CYP2E1*
Aldehyde
dehydrogenase
Ethanol
Acetaldehyde
Ethanoic acid
CYP3A4
CYP1A2
Water + CO2
CYP2B6
Figure 11.1  Metabolism of alcohol.
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CHAPTER 11
All of the enzymes involved in the metabolism of alcohol exhibit genetic
­polymorphism. For example, the majority of people of north Asian origin are poor
metabolisers via aldehyde dehydrogenase.11 Enzyme function can change in response to
alcohol. Chronic consumption of alcohol induces CYP2E1 and CYP3A4. The effects of
alcohol on other hepatic metabolising enzymes have been poorly studied.
Table 11.8 lists drugs that inhibit ADH and aldehyde dehydrogenase.
Interactions are difficult to predict in alcohol misusers because two opposing
processes may be at work: competition for enzymatic sites during periods of consumption/
intoxication (increasing drug plasma levels) and enzyme induction prevailing during
periods of sobriety (reducing drug plasma levels10). In chronic drinkers, particularly
those who binge-­drink, blood levels of prescribed drugs may reach toxic levels during
periods of intoxication with alcohol and then be sub-­therapeutic when the patient is
sober. Even in non-­intoxicated individuals there is some evidence that co-­administered
alcohol confers competitive inhibition of CYP3A4, leading to increased exposure to
drugs metabolised by this enzyme (Table 11.9).15 This makes it very difficult to optimise
treatment of physical or mental illness.
Table 11.8  Drugs that inhibit alcohol dehydrogenase and aldehyde dehydrogenase.
Enzyme
Inhibited by
Potential consequences
Alcohol dehydrogenase
Aspirin
H2 antagonists
Reduced metabolism of alcohol resulting
in higher plasma levels for longer
periods of time
Aldehyde dehydrogenase
Chlorpropamide
Disulfiram
Griseofulvin
Isoniazid
Isosorbide dinitrate
Metronidazole*
Nitrofurantoin
Sulphamethoxazole
Tolbutamide
Reduced ability to metabolise
acetaldehyde leading to ‘Antabuse’ type
reaction: facial flushing, headache,
tachycardia, nausea and vomiting,
arrhythmias and hypotension
*Evidence that metronidazole has any effect on aldehyde dehydrogenase is surprisingly weak.12–14
Table 11.9  Co-­administration of alcohol and substrates for CYP2E1 and CYP3A4.5,6,16
Substrates for enzyme
(note: this is not an
exhaustive list)
Effects in an intoxicated
patient
Effects in a chronic, sober
drinker
CYP2E1
Isoniazid
Paracetamol
Phenobarbitone
Warfarin
Zopiclone
Competition between alcohol
and drug leading to reduced
rates of metabolism of both
compounds. Increased plasma
levels may lead to toxicity
Activity of CYP2E1 is increased
up 10-­fold
 
Increased metabolism of drugs
potentially leading to
therapeutic failure

26 - Pharmacodynamic interactions24
Pharmacodynamic interactions2–4
Pharmacokinetics
CHAPTER 11
Interactions of uncertain aetiology include increased blood alcohol concentrations in
people who take verapamil and decreased metabolism of methylphenidate in people
who consume alcohol. Alcohol may also, via various routes, impair the function of
slow-­release tablet mechanisms causing dose-­dumping.17
Pharmacodynamic interactions2–4
Alcohol enhances inhibitory neurotransmission at gamma-­aminobutyric acid A (GABA-­A)
receptors and reduces excitatory neurotransmission at glutamate N-­methyl-­D-­aspartate
(NMDA) receptors. It also increases dopamine release in the mesolimbic pathway and
may have some effects on serotonin and opiate pathways. Given these actions, alcohol
would be expected to cause sedation, amnesia and ataxia (Table 11.10) and give rise to
feelings of pleasure (and/or worsen psychotic symptoms in vulnerable individuals).
Table 11.9  (Continued )
Substrates for enzyme
(note: this is not an
exhaustive list)
Effects in an intoxicated
patient
Effects in a chronic, sober
drinker
CYP3A4
Alprazolam
Aripiprazole
Benzodiazepines
Carbamazepine
Clozapine
Donepezil
Galantamine
Haloperidol
Methadone
Mirtazapine
Quetiapine
Risperidone
Sildenafil
Tricyclics
Valproate
Venlafaxine
Z-­hypnotics
Competition between alcohol
and drug leading to reduced
rates of metabolism of both
compounds. Increased plasma
levels may lead to toxicity
Increased rate of drug
metabolism potentially leading
to therapeutic failure
Enzyme induction can last for
several weeks after alcohol
consumption ceases
Table 11.10  Pharmacodynamic interactions with alcohol.
Effect of
alcohol
Effect exacerbated by
Potential consequences
Sedation
Other sedative drugs, e.g.:
Antihistamines
Antipsychotics
Baclofen
Benzodiazepines
Lofexidine
Opiates
Tizanidine
Tricyclics
Z-­hypnotics
Increased CNS depression ranging from increased
propensity to be involved in accidents through to
respiratory depression and death
(Continued )
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CHAPTER 11
Alcohol can cause or worsen psychotic symptoms by increasing dopamine release in
mesolimbic pathways. The effect of antipsychotic drugs may be competitively antagonised, rendering them less effective.
Electrolyte disturbances secondary to alcohol-­related dehydration can be exacerbated by other drugs that cause electrolyte disturbances (e.g. diuretics). Heavy alcohol consumption can lead to hypoglycaemia in people with diabetes who take
insulin or oral hypoglycaemics. Theoretically there is an increased risk of lactic
acidosis in patients who take metformin with alcohol. Alcohol can also increase
blood pressure.
Chronic alcohol drinkers are particularly susceptible to the gastrointestinal irritant
effects of aspirin and non-­steroidal anti-­inflammatory drugs.
In the presence of pharmacokinetic interactions, pharmacodynamic interactions
may be more marked. For example, in a chronic heavy drinker who is sober, enzyme
induction will increase the metabolism of diazepam, which may lead to increased
levels of anxiety (treatment failure). If the same patient becomes intoxicated with
alcohol, the metabolism of diazepam will be greatly reduced as it will have to
­compete with alcohol for the metabolic capacity of CYP3A4. Plasma levels of
­alcohol and diazepam will rise (toxicity). As both alcohol and diazepam are sedative (via GABA-­A affinity), loss of consciousness and respiratory depression may
occur.
Table 11.11 lists drugs that are safe and those that should be avoided in patients who
continue drinking.
Table 11.10  (Continued )
Effect of
alcohol
Effect exacerbated by
Potential consequences
Amnesia
Other amnesic drugs, e.g.:
Barbiturates
Benzodiazepines
Z-­hypnotics
Increased amnesic effects ranging from
mild memory loss to total amnesia. Usually
anterograde amnesia: loss of memory of
events after the effects of alcohol begin
Ataxia
ACE inhibitors
Beta-­blockers
Calcium channel blockers
Nitrates
Adrenergic alpha receptor
antagonists, e.g.:
Clozapine
Risperidone
Tricyclics
Increased unsteadiness and falls
ACE, angiotensin-­converting enzyme; CNS, central nervous system.

27 - References
References
Pharmacokinetics
CHAPTER 11
References
Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health 2006; 29:245–254.
Tanaka E. Toxicological interactions involving psychiatric drugs and alcohol: an update. J Clin Pharm Ther 2003; 28:81–95.
Wan-­Chih T. Alcohol-­related drug interactions. Pharmacist’s Letter/Prescriber’s Letter 2008; 24:240106.
Smith RG. An appraisal of potential drug interactions in cigarette smokers and alcohol drinkers. J Am Podiatr Med Assoc 2009; 99:81–88.
Chan LN, et  al. Pharmacokinetic and pharmacodynamic drug interactions with ethanol (alcohol). Clin Pharmacokinet 2014;
53:1115–1136.
Jiang Y, et al. Alcohol metabolizing enzymes, microsomal ethanol oxidizing system, cytochrome P450 2E1, catalase, and aldehyde dehydrogenase
in alcohol-­associated liver disease. Biomedicines 2020; 8:50.
Salmela KS, et al. Respective roles of human cytochrome P-­4502E1, 1A2, and 3A4 in the hepatic microsomal ethanol oxidizing system.
Alcohol Clin Exp Res 1998; 22:2125–2132.
Hamitouche S, et al. Ethanol oxidation into acetaldehyde by 16 recombinant human cytochrome P450 isoforms: role of CYP2C isoforms in
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Koster M, et al. Seizures during antidepressant treatment in psychiatric inpatients – results from the transnational pharmacovigilance project
‘Arzneimittelsicherheit in der Psychiatrie’ (AMSP) 1993–2008. Psychopharmacology (Berl) 2013; 230:191–201.
Cederbaum AI. Alcohol metabolism. Clin Liver Dis 2012; 16:667–685.
Wall TL, et al. Biology, genetics, and environment: underlying factors influencing alcohol metabolism. Alcohol Res 2016; 38:59–68.
Williams CS, et al. Do ethanol and metronidazole interact to produce a disulfiram-­like reaction? Ann Pharmacother 2000; 34:255–257.
Visapää JP, et al. Lack of disulfiram-­like reaction with metronidazole and ethanol. Ann Pharmacother 2002; 36:971–974.
Mergenhagen KA, et al. Fact versus fiction: a review of the evidence behind alcohol and antibiotic interactions. Antimicrob Agents Chemother
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Huang Z, et al. Influence of ethanol on the metabolism of alprazolam. Expert Opin Drug Metab Toxicol 2018; 14:551–559.
Traccis F, et al. Alcohol-­medication interactions: a systematic review and meta-­analysis of placebo-­controlled trials. Neurosci Biobehav Rev
2022; 132:519–541.
Lennernäs H. Ethanol-­drug absorption interaction: potential for a significant effect on the plasma pharmacokinetics of ethanol vulnerable
formulations. Mol Pharm 2009; 6:1429–1440.
Table 11.11  Psychotropic drugs: choice in patients who continue to drink.
Safest choice
Best avoided
Antipsychotics
Sulpiride and amisulpride
Paliperidone, if depot required
(non-­sedative and renally excreted)
Very sedative antipsychotics such as
chlorpromazine and clozapine
Antidepressants
SSRIs – citalopram, sertraline
Potent inhibitors of CYP3A4
(fluoxetine, paroxetine) may
decrease alcohol metabolism in
chronic drinkers
TCAs, because impairment of metabolism by
alcohol (while intoxicated) can lead to increased
plasma levels and consequent signs and
symptoms of overdose (profound hypotension,
seizures, arrhythmias and coma)
Cardiac effects can be exacerbated by electrolyte
disturbances
Combinations of TCAs and alcohol profoundly
impair psychomotor skills
Mirtazapine – often very sedative
MAOIs, as can cause profound hypotension. Also
potential interaction with tyramine-­containing
drinks which can lead to hypertensive crisis
Mood stabilisers
Valproate (where regulations allow)
Carbamazepine
Higher plasma levels achieved
during periods of alcohol
intoxication may be poorly tolerated
Lithium, because it has a narrow therapeutic
index and alcohol-­related dehydration and
electrolyte disturbance can precipitate lithium
toxicity
Note: be aware of the possibility of hepatic failure or reduced hepatic function in chronic alcohol misusers. See
‘Hepatic impairment’ in Chapter  8. Also note the risk of hepatic toxicity with some recommended drugs (e.g.
valproate).
MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants.