HUMAN PSYCHOPHARMACOLOGY
Hum. Psychopharmacol. Clin. Exp. 13, 385±387 (1998)
EDITORIAL
It's all in the Mind: Measuring Somnolence and
CNS Drug Side E€ects
Most readers would agree that the CNS side e€ects
of a psychoactive substance are primarily deter-
mined by the pharmacological (pharmacokinetic
and pharmacodynamic) pro®le of the drug in
question. The potential for a patient to experience
these drug e€ects is doubtless in¯uenced not only
by the severity and nature of the psychological
disorder for which the drug was prescribed, but also
by the patient's expectations, needs, personality,
familiarity with the substance and by the inter-
action of the drug with the particular presentation
of the illness.
CNS side e€ects are thus seen as falling into
two types. First, objectively determined ones and
second, the subjective e€ects of taking a particular
drug. Psychopharmocologists believe that the
action of a psychoactive drug is re¯ected in the
changes produced in behaviour. Thus the task
of psychopharmacologists is to develop sensitive,
reliable and valid psychometrics by which changes
in behavioural function following drug use
might well be assessed. `Behaviour' can be covert,
as in thinking, problem solving, reasoning and
remembering, or overt, such as the performance of
the skills necessary for everyday functioning.
However, it is only psychometric tests which give
an objective assessment of the intrinsic action of a
psychotropic in a way that subjective experience is
unable to provide. Moreover, within the context of
a methodologically sound and properly controlled
trial, such psychometrics represent the actual
impact of a particular drug on behaviour.
Some may believe that the distinction between
`subjective' and `objective' assessment might well be
academic as the two are interdependent. How-
ever, the origins of the objective e€ects rest in the
pharmacokinetics and pharmocodynamics of the
drug and are a representation of the intrinsic
potential of a particular drug to produce changes
in behaviour, whereas the subjective responses
CCC 0885±6222/98/060385±03$17.50
# 1998 John Wiley & Sons, Ltd.
are individualised experiences of the psychosocial
e€ects of the medication and can be modi®ed
by an individual patient's habits, expectations,
prior experiences, motivation, predisposition,
personality, needs and desires.
The principal CNS e€ects of psychoactive medi-
cations are on the cognitive system: not just because
impairment of cognitive function is central to and
characteristic of depression and anxiety, but also
because cognitive impairment implies a lack of
judgement and reason in critical situations when,
for example, driving a car or performing work
related tasks in an industrial/domestic context. The
problem with identifying cognitive impairment
is the frequent lack of a subjective representation
and awareness of the compromised cognitive
function (O'Hanlon, 1988). Patients might well be
intellectually impaired or cognitively de®cient, but
there is no absolute guarantee that there will be a
subjective awareness of the extent or magnitude of
the disruption. However, a subjective appreciation
of impaired performance did not enable a group of
car driving subjects to correct or compensate for the
perceived disturbance (Betts et al., 1984). Cognitive
impairment, due to the pharmacological e€ects of a
particular drug, can be manifest only by changes in
psychometric test performance. Subjective impres-
sions of impaired cognitive function are, at best,
unreliable and not, arguably ever, an indication of
the totality of the impact of a particular drug on
thinking, memory, reasoning or other vital aspects
of cognitive function (Adelsberg, 1997).
Impaired cognitive function is often thought to
be a secondary e€ect to feeling tired and sleepy.
However, amnesia and bad judgement, poor
mentition, and faulty decision making have been
shown to be independent of ratings of sedation,
sleepiness and tiredness and it has been suggested
that subjective sedation and objective impair-
ment of skilled behaviours might originate in
386 IAN HINDMARCH
di€erent neurological mechanisms, at least as far as
antihistamines are concerned (Aaronson, 1993).
The extent to which a psychoactive drug induces
`somnolence' is not, therefore, necessarily an
indication of compromised cognition which can
only be determined by the changes produced on
objective assessment.
Physicians often feel that unwanted CNS e€ects
on cognition are tolerated as patients adapt and
habituate to them as, for example, the confusion,
sedation, impaired memory and psychomotor slow-
ing found with TCAs. However, just as repeated use
of alcohol might be associated with a subjective
reduction in the intensity of the drug induced
dizziness, uncoordination, confusion and psycho-
motor retardation, the fact remains that alcohol still
exerts its pharmacological activity on the nervous
substrate of the brain and the cognitive impairment,
lack of judgement etc. does not dissipate (Gengo
and Gabos, 1987). Indeed, with the TCAs, it would
be surprising if the lapses of memory, confusion,
sedation and poor sensori-motor coordination did
actually disappear, as these objective e€ects are due
directly to the intrinsic anticholinergic anti-
histaminic and a1-adrenergic blockading actions
of the drugs. Impaired cognitive function is thus
seen as a direct consequence of the administration
of certain drugs. These impairments are not neces-
sarily re¯ected in changes in subjective awareness,
or patients' reports of side e€ects, although the
impairment of important aspects of behaviour is
objectively demonstrable.
The distinction between objective and subjective
is particularly important when considering
sedation. Sedation is used here to represent
the objective assessment of what might subjectively
be represented as `tiredness', `sleepiness', `drowsi-
ness', `somnolence', `doziness', etc. Some years
ago I had two healthy volunteers report feeling
sleepy after a 15 mg dose of dexamphetamine
sulphate. The psychometric assessments showed
the two to be aroused, alert and very awake. A
subsequent inquiry showed that the two volunteers
had stayed awake the previous night until 0200 h,
and although they complained of somnolence they
were not, in any way, objectively sedated. A similar
paradox was illustrated (Hindmarch and Bhatti,
1988) when subjects reported signi®cant somno-
lence with respect to placebo following 25±100 mg
sertraline, while at the same time showing a dose-
related behavioural arousal on objective measures
of CNS function (Critical Flicker Fusion Thres-
hold) and Goetz et al. (1991) found reports of
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subjective sedation following hydroxyzine, but no
evidence of signi®cant psychomotor e€ects.
The opposite of the above example is even more
important when a subject or patient feels alert,
but objectively is compromised by sedation. The
importance of separating subjective tiredness
from objective sedation is apparent when one
considers the so-called `warning' labels placed
on prescription and over-the-counter medicines at
the time they are dispensed. Warnings of the order,
`If you feel tired or drowsy do not operate
machinery or drive a motor vehicle' clearly place
the onus of determining whether or not an
individual is tired or sedated on the patient at the
point of taking the prescribed medication. It is
evident that an individual patient is not able to self-
assess objectively the particular limits of deteriora-
tion and disruption of relevant cognitive and
psychomotor behaviours following a psychotropic
drug. Furthermore, the interests of patient safety
are not served if the warnings placed on medicines
are not adequate.
Many studies appear in the clinical literature
where dangerous, behaviourally toxic drugs;
for example, sedative, benzodiazepines, tricyclic
antidepressants etc; do not necessarily produce
feelings of somnolence or tiredness in patients
using them. This could well be due to habituation
and the development of tolerance. However,
when objective assessments are made on the same
drugs, the deleterious e€ects can well be demon-
strated. Intrinsic sedation and impaired judgement,
particularly when there is no corresponding sub-
jective awareness, is not only counter-therapeutic,
but it also places the patient at increased risk of
accident on the road (Ray et al., 1992) and in
domestic and industrial situations (Currie et al.,
1995).
Perceived tiredness, as a consequence of an illness
or disease may be wrongly attributed as sedation
due to a concomitant medication even though there
is no objective evidence of the drug having pro-
duced sedation. While patients' perceptions are
useful for guiding physicians in prescribing accept-
able and appropriate treatment regimens, they
cannot be regarded as a substitute for psycho-
metrics in determining the objective sedation due
to a particular drug. There are, of course, many
instances where the untreated illness or disorder
can, in itself, produce a signi®cant decrement in the
performance of the activities of daily living. How-
ever, within the context of this editorial, it is a
consequence of treating say, depression, anxiety,
HUMAN PSYCHOPHARMACOLOGY, VOL. 13, 385±387 (1998)
 EDITORIAL
allergy, sleep disturbance etc. with a medication
that augments the impaired performance due to the
underlying clinical condition with the sedation
intrinsic to certain psychoactive drugs.
The only way to assess the accident risk potential
of a psychoactive drug is the use of an appropriate
psychometric within the context of a properly
designed pharmacodynamic trial in both volunteers
and patients (Dal Pozzo, 1997). Psychometrics are
reliable and valid indicators of unwanted CNS
e€ects of drugs. It is the results from proper
psychometrics that should determine whether or
not a particular molecule is labelled as `sedative'
and unsuitable for car driving patients etc. and not
the subjective, and often idiosyncratic, feelings of a
patient who has to make a self-judgment as to
whether or not he/she is incapacitated. Thus, patient
safety needs are best served when behaviourally
toxic medicines are clearly labelled as incompatible
with performing the high accident risk tasks of
everyday living. Such labelling would provide a
scienti®c evidence-based warning which, a priori,
would identify which CNS drugs are safe to use
in ambulant patients performing their usual daily
routines.
IAN HINDMARCH
Human Psychopharmacology Research Unit
University of Surrey
Milford Hospital
Godalming
Surrey, UK
# 1998 John Wiley & Sons, Ltd.
387
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HUMAN PSYCHOPHARMACOLOGY, VOL 13, 385±387 (1998)