CLINICAL PHARMACOLOGY OF LITHIUM
Until recently,
lithium carbonate was the universally preferred treatment for bipolar disorder,
especially in the manic phase. With the approval of valproate, aripiprazole,
olanzapine, quetiapine, risperidone, and ziprasidone for this indication, a
smaller percent-age of bipolar patients now receive lithium. This trend is
rein-forced by the slow onset of action of lithium, which has often been
supplemented with concurrent use of antipsychotic drugs or potent
benzodiazepines in severely manic patients. The overall success rate for
achieving remission from the manic phase of bipo-lar disorder can be as high as
80% but lower among patients who require hospitalization. A similar situation
applies to maintenance treatment, which is about 60% effective overall but less
in severely ill patients. These considerations have led to increased use of
com-bined treatment in severe cases. After mania is controlled, the
antipsychotic drug may be stopped and benzodiazepines and lithium continued as
maintenance therapy.
The depressive phase
of manic-depressive disorder often requires concurrent use of an antidepressant
drug . Tricyclic antidepressant agents have been linked to precipitation of
mania, with more rapid cycling of mood swings, although most patients do not
show this effect. Selective serotonin reuptake inhibitors are less likely to
induce mania but may have limited efficacy. Bupropion has shown some promise
but—like tricyclic antidepressants—may induce mania at higher doses. As shown
in recent controlled trials, the anticonvulsant lamotrigine is effective for
many patients with bipolar depression. For some patients, however, one of the
older monoamine oxidase inhibitors may be the antidepressant of choice.
Quetiapine and the combination of olanzapine and fluoxetine has been approved
for use in bipolar depression.
Unlike antipsychotic
or antidepressant drugs, which exert sev-eral actions on the central or
autonomic nervous system, lithium ion at therapeutic concentrations is devoid
of autonomic blocking effects and of activating or sedating effects, although
it can pro-duce nausea and tremor. Most important is that the prophylactic use
of lithium can prevent both mania and depression. Many experts believe that the
aggressive marketing of newer drugs has inappropriately produced a shift to
drugs that are less effective than lithium for substantial numbers of patients.
Recurrent endogenous depression with a cyclic pattern is con-trolled by either
lithium or imipramine, both of which are supe-rior to placebo.Schizoaffective disorder, another
condition with an affectivecomponent characterized by a mixture of
schizophrenic symptoms and depression or excitement, is treated with
antipsychotic drugs alone or combined with lithium. Various antidepressants are
added if depression is present.
Lithium alone is
rarely successful in treating schizophrenia,
but adding it to an antipsychotic may salvage an otherwise treat-ment-resistant
patient. Carbamazepine may work equally well when added to an antipsychotic
drug.
An interesting
application of lithium that is relatively well sup-ported by controlled studies
is as an adjunct to tricyclic antide-pressants and SSRIs in patients with unipolar depression who do not respond
fully to monotherapy with the antidepressant. For this application,
concentrations of lithium at the lower end of the recommended range for
manic-depressive illness appear to be adequate.
Clinicians rely on
measurements of serum lithium concentrations for assessing both the dosage required
for treatment of acute mania and for prophylactic maintenance. These
measurements are customarily taken 10–12 hours after the last dose, so all data
in the literature pertaining to these concentrations reflect this interval.
An initial
determination of serum lithium concentration should be obtained about 5 days
after the start of treatment, at which time steady-state conditions should have
been attained. If the clinical response suggests a change in dosage, simple
arithmetic (new dose equals present dose times desired blood level divided by
present blood level) should produce the desired level. The serum concentration
attained with the adjusted dos-age can be checked after another 5 days. Once
the desired concentration has been achieved, levels can be measured at
increasing intervals unless the schedule is influenced by inter-current illness
or the introduction of a new drug into the treat-ment program.
The decision to use
lithium as prophylactic treatment
depends on many factors: the frequency and severity of previous episodes, a
cre-scendo pattern of appearance, and the degree to which the patient is
willing to follow a program of indefinite maintenance therapy. If the present
attack was the patient’s first or if the patient is unreliable, one might
prefer to terminate treatment after the episode has subsided. Patients who have
one or more episodes of illness per year are candi-dates for maintenance
treatment. Although some patients can be maintained with serum levels as low as
0.6 mEq/L, the best results have been obtained with higher levels, such as 0.9
mEq/L.
Renal clearance of
lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need
to be reduced by a similar amount. A similar reduction in lithium clearance has
been noted with several of the newer nonsteroidal anti-inflammatory drugs that
block synthesis of prostaglandins. This interaction has not been reported for either aspirin or
acetaminophen. All neuroleptics tested to date, with the possible exception of
clo-zapine and the newer atypical antipsychotics, may produce more severe
extrapyramidal syndromes when combined with lithium.
Many adverse effects
associated with lithium treatment occur at varying times after treatment is
started. Some are harmless, but it is important to be alert to adverse effects
that may signify impend-ing serious toxic reactions.
Tremor is one of the most common adverse effects of lithiumtreatment,
and it occurs with therapeutic doses. Propranolol and atenolol, which have been
reported to be effective in essential tremor, also alleviate lithium-induced
tremor. Other reported neurologic abnormalities include choreoathetosis, motor
hyper-activity, ataxia, dysarthria, and aphasia. Psychiatric disturbances at
toxic concentrations are generally marked by mental confusion and withdrawal.
Appearance of any new neurologic or psy-chiatric symptoms or signs is a clear
indication for temporarily stopping treatment with lithium and for close
monitoring of serum levels.
Lithium probably
decreases thyroid function in most patients exposed to the drug, but the effect
is reversible or nonprogressive. Few patients develop frank thyroid
enlargement, and fewer still show symptoms of hypothyroidism. Although initial
thyroid testing followed by regular monitoring of thyroid function has been
pro-posed, such procedures are not cost-effective. Obtaining a serum TSH
concentration every 6–12 months, however, is prudent.
Polydipsia and
polyuria are common but reversible concomitants of lithium treatment, occurring
at therapeutic serum concentra-tions. The principal physiologic lesion involved
is loss of respon-siveness to antidiuretic hormone (nephrogenic diabetes
insipidus). Lithium-induced diabetes insipidus is resistant to vasopressin but
responds to amiloride.
Extensive literature
has accumulated concerning other forms of renal dysfunction during long-term
lithium therapy, including chronic interstitial nephritis and minimal-change
glomerulopathy with nephrotic syndrome. Some instances of decreased glomerular
filtration rate have been encountered but no instances of marked azotemia or
renal failure.
Patients receiving
lithium should avoid dehydration and the asso-ciated increased concentration of
lithium in urine. Periodic tests of renal concentrating ability should be
performed to detect changes.
Edema is a common
adverse effect of lithium treatment and may be related to some effect of
lithium on sodium retention. Although weight gain may be expected in patients
who become edematous, water retention does not account for the weight gain
observed in up to 30% of patients taking lithium.
The
bradycardia-tachycardia (“sick sinus”) syndrome is a definite contraindication
to the use of lithium because the ion further depresses the sinus node. T-wave
flattening is often observed on the electrocardiogram but is of questionable
significance.
Renal clearance of
lithium increases during pregnancy and reverts to lower levels immediately
after delivery. A patient whose serum lithium concentration is in a good
therapeutic range during preg-nancy may develop toxic levels after delivery.
Special care in monitoring lithium levels is needed at these times. Lithium is
transferred to nursing infants through breast milk, in which it has a
concentration about one third to one half that of serum. Lithium toxicity in
newborns is manifested by lethargy, cyanosis, poor suck and Moro reflexes, and
perhaps hepatomegaly.
The issue of
lithium-induced dysmorphogenesis is not settled. An earlier report suggested an
increase in cardiac anomalies— especially Ebstein’s anomaly—in lithium babies,
and it is listed as such in Table 59–1 in this book. However, more recent data
suggest that lithium carries a relatively low risk of teratogenic effects.
Further research is needed in this important area.
Transient acneiform
eruptions have been noted early in lithium treatment. Some of them subside with
temporary discontinuance of treatment and do not recur with its resumption.
Folliculitis is less dramatic and probably occurs more frequently. Leukocytosis
is always present during lithium treatment, probably reflecting a direct effect
on leukopoiesis rather than mobilization from the marginal pool. This adverse
effect has now become a therapeutic effect in patients with low leukocyte
counts.
Therapeutic overdoses
of lithium are more common than those due to deliberate or accidental ingestion
of the drug. Therapeutic over-doses are usually due to accumulation of lithium
resulting from some change in the patient’s status, such as diminished serum
sodium, use of diuretics, or fluctuating renal function. Since the tissues will
have already equilibrated with the blood, the plasma concentrations of lithium
may not be excessively high in proportion to the degree of toxicity; any value
over 2 mEq/L must be considered as indicating likely toxicity. Because lithium
is a small ion, it is dialyzed readily. Both peritoneal dialysis and
hemodialysis are effective, although the latter is preferred.
Valproic acid
(valproate), as an antiepileptic, has been demonstrated to have antimanic
effects andis now being widely used for this indication in the USA. (Gabapentin
is not effective, leaving the mechanism of action of valproate unclear.)
Overall, valproic acid shows efficacy equivalent to that of lithium during the
early weeks of treatment. It is significant that valproic acid has been
effective in some patients who have failed to respond to lithium. Moreover, its
side-effect profile is such that one can rapidly increase the dosage over a few
days to produce blood levels in the apparent therapeutic range, with nausea
being the only limiting factor in some patients. The starting dosage is 750
mg/d, increasing rapidly to the 1500–2000 mg range with a recommended maximum
dosage of 60 mg/kg/d.
Combinations of
valproic acid with other psychotropic medica-tions likely to be used in the
management of either phase of bipolar illness are generally well tolerated.
Valproic acid is an appropriate first-line treatment for mania, although it is
not clear that it will be as effective as lithium as a maintenance treatment in
all subsets of patients. Many clinicians advocate combining valproic acid and
lith-ium in patients who do not fully respond to either agent alone.
Carbamazepine has been
considered to be a reasonable alternative to lithium when the latter is less
than optimally efficacious. The mode of action of carbamazepine is unclear, and
oxcarbazepine is not effective. Carbamazepine may be used to treat acute mania
and also for prophylactic therapy. Adverse effects are generally no greater and
sometimes less than those associated with lithium. Carbamazepine may be used
alone or, in refractory patients, in combination with lithium or, rarely,
valproate.
The use of
carbamazepine as a mood stabilizer is similar to its use as an anticonvulsant .
Dosage usually begins with 200 mg twice daily, with increases as needed.
Maintenance dosage is similar to that used for treating epilepsy, ie, 800–1200
mg/d. Plasma concentrations between 3 and 14 mg/L are considered desirable,
although no therapeutic range has been established. Blood dyscrasias have
figured prominently in the adverse effects of carbamazepine when it is used as
an anticonvulsant, but they have not been a major problem with its use as a
mood stabilizer. Overdoses of carbamazepine are a major emergency and should
generally be managed like over-doses of tricyclic antidepressants .
Lamotrigine has been
reported to be useful in preventing the depression that often follows the manic
phase of bipolar disorder. A number of novel agents are under investigation for
bipolar depression, including riluzole, a neuroprotective agent that is
approved for use in amyotrophic lateral sclerosis; ketamine, a noncompetitive
NMDA antagonist previously discussed as a drug believed to model schizophrenia
but thought to act by producing relative enhancement of AMPA receptor activity;
and AMPA receptor potentiators.
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