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Psychotropic Drugs: Brain and Plasma Pharmacokinetics and the Therapeutic Window

Psychotropic Drugs: Brain and Plasma Pharmacokinetics and the Therapeutic Window

One of the most challenging
aspects of psychiatric pharmacotherapy
faced by clinicians is
to administer a drug dosage that is most
clinically effective yet causes minimal
side effects. This is not a trivial problem.
Owing to marked individual differences
in the pharmacologic profiles of
each psychotropic drug, there can be
enormous variations in plasma concentrations.1 Since the therapeutic range is
relatively narrow for the mood stabilizers
lithium, carbamazepine, and
valproic acid, their plasma concentrations
are routinely monitored. As a
classic example of routine therapeutic
drug monitoring (TDM), plasma lithium
concentrations must be carefully monitored
to avoid dangerous and potentially
life-threatening toxicity.

TDM of other widely used psychotropic
drugs, such as antipsychotics
and antidepressants, is much less
common. Recently, however, positron
emission tomography (PET) and single
photon emission computed tomography
(SPECT) have been used extensively
to characterize the relationships between
occupancy of target molecules
in the brain (neurotransmitter receptors
and transporters), plasma concentrations
of the respective drug, and clinical
efficacy and side effects. Indeed,
PET occupancy measures have approached
the status of surrogate markers
for probable drug effectiveness and
have proved critical in moving potential
psychotropic agents from the preclinical
to the clinical stage of development.

It is now widely accepted that determining
the appropriate occupancy level
for various classes of drugs is vital to
streamlining drug development. For
some drug classes, these findings are of
considerable clinical importance. In this
article, I will provide a brief review of
the latest data on antipsychotics, antidepressants,
and other psychotropic drugs
in relation to brain occupancy and plasma levels. It will be shown that PET has validated
the concept that plasma concentrations
directly reflect concentrations of
psychotropic drugs at brain target molecules;
thus, the simple determination of
a drug plasma concentration helps to
achieve optimal brain concentrations in
the respective therapeutic window.


With regard to the relationship between
drug kinetics in plasma and brain and the
clinical effects and side effects, antipsychotics
are among the most studied drugs.
Farde and colleagues2 demonstrated that
clinically effective doses of typical
neuroleptics occupy between 65% and
90% of D2-like dopamine receptors. The
suggestion of a therapeutic window
between 60% and 80% striatal D2 receptor
occupancy for sufficient treatment
response and a ceiling of approximately
80% occupancy for extrapyramidal side
effects (EPS) was later confirmed by
Farde and colleagues and a number of
other groups (Figure 1).

Although antipsychotics are characterized
by marked pharmacologic
heterogeneity, the general rule that the
incidence of EPS increases in a dosedependent
manner also applies for most
of the second-generation antipsychotics,
including olanzapine and risperidone.
They lose their atypical properties when
striatal D2 receptor occupancy passes a
threshold of approximately 80%. The
serotonin type 2 (5-HT2) antagonism that
characterizes most of the second-generation
antipsychotics seems to protect
from EPS only at moderate doses; this
preservation is lost at striatal D2 receptor
occupancies above the 80% threshold.
Thus, when the doses of these drugs
are raised above a certain threshold
(approximately 6 mg/d for risperidone,
30 mg/d for olanzapine, and 160 mg/d
for ziprasidone), striatal D2 occupancy
increases to levels that are associated with
a higher incidence of EPS.

There are some exceptions to this
general rule. A number of second-generation
antipsychotics do not induce EPS,
even when their doses (or plasma concentrations)
are raised to unusually high
levels. In those cases, the upper threshold
of the therapeutic window is defined
by other side effects, rather than EPS.

This pharmacologically heterogeneous
group of antipsychotics can be
differentiated by the distinct characteristics
of these drugs in PET studies.
Clozapine and quetiapine occupy a maximum
of 60% to 70% of striatal D2-like
dopamine receptors even at extremely
high doses or plasma levels (Figure 2 [see May 2006 Psychiatric Times, page 58]).3
A significant occupancy of striatal D2
receptors is no longer detectable 24 hours
after the last administration of quetiapine.4 These particular characteristics of
clozapine and quetiapine are most likely
due to their low affinity rather than their
rapid dissociation from the D2 receptor.
Thus, the tolerability and safety of these
drugs is limited by anticholinergic, antihistaminic,
and α-adrenolytic side
effects, rather than EPS.

On the other hand, administration of
aripiprazole leads to complete saturation
of striatal D2 receptors at clinical
doses, although the incidence of EPS is
very low (Figure 3 [see May 2006 Psychiatric Times, page 61]).5 Again, tolerability
is not restricted by the occurrence of
EPS but rather by other side effects, such
as psychomotor activation. The characterization of aripiprazole as a partial
dopamine agonist explains this unique
feature. Nevertheless, there are several
reported cases of EPS caused by aripiprazole
when used in combination with
serotonergic antidepressants, suggesting
that aripiprazole may exert stronger
dopamine antagonistic properties under
certain “real world” conditions.6

Consequently, the therapeutic window
for treatment with most antipsychotic
drugs is defined at the low end
by a minimum D2 receptor occupancy,
which has to be achieved, and at the
high end by the EPS threshold. With
the exceptions of aripiprazole, clozapine,
and quetiapine, this rule applies to
both first- and second-generation

When the plasma concentration
range reaches the therapeutic occupancy
window (established by means of PET),
we can test whether this range is the most
useful in large patient populations. This
has been demonstrated for various
antipsychotic drugs, and a well-documented
and clinically important example
is risperidone. PET studies show that
risperidone at 6 mg/d, which is the highest
dosage administered under usual clinical
conditions, enables a significant
proportion of patients to have striatal D2-
like occupancies sufficient to cause EPS,
while a daily oral dose of 3 to 4 mg
produces a striatal D2-like occupancy in
the range of 70% to 80% in most patients.

In a sample of 9 patients, Kapur and
associates7 documented mean receptor
occupancies of 66% at 2 mg/d, 73% at
4 mg/d, and 79% at 6 mg/d of risperidone.
Three patients, those with the
highest receptor occupancies, exhibited
mild EPS in that study. Striatal D2-like
occupancy was 25%, 40%, and 48% in
3 patients who were given 25 mg of
risperidone long-acting injectable
(RLAI)8; 50 mg RLAI led to occupancies
of 59%, 71%, and 83%; and 75 mg
RLAI to 62% and 72%. The corresponding
active-moiety concentrations
(active moiety: risperidone and its active
metabolite hydroxyrisperidone) were
5.2 to 7.4 ng/mL, 15.0 to 37.0 ng/mL,
and 20.9 to 22.5 ng/mL, respectively.

Thus, the available data suggest that
the 80% threshold that is associated with
a higher probability of EPS is reached
with approximately 40 ng/mL of both
risperidone and RLAI.A plasma concentration
of approximately 15 ng/mL of
both formulations is associated with
60% striatal D2 occupancy. It can be
concluded from this study that the therapeutic
window for risperidone (active
moiety) is approximately 15 to 40 ng/mL
and that determination of plasma concentrations
is warranted in those patients
who do not respond sufficiently (ie,very low plasma levels) or who suffer
from EPS (ie, very high plasma levels).

The knowledge of an individual
plasma level can provide meaningful
information on psychotropic drug concentrations
at brain target molecules.
Baumann and associates9 provide a thorough
listing of recommended target
plasma concentration ranges for psychoactive
drugs and levels of recommendation
for routine monitoring. However,
the therapeutic ranges are based on
clinical studies in most cases and lack
confirmation by imaging studies.


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