Basic & Clinical Pharmacology

Pharmacology 1, Pharm. 341

Antipsychotic Agents & Lithium

Chapter 29

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 What is Psychosis??
• Psychosis is a loss of contact with reality
that usually includes:
• False beliefs about what is taking place or
who one is (delusions)
• Seeing or hearing things that aren't there
(hallucinations).
• Psychotic symptoms may include:
Disorganized thought and speech
False beliefs that are not based in reality (delusions), especially
unfounded fear or suspicion
Hearing, seeing, or feeling things that are not there (hallucinations)
Thoughts that "jump" between unrelated topics (disordered thinking)
A number of medical problems can cause psychosis, including:
• Alcohol and certain illegal drugs, both during use and during withdrawal
•Brain diseases, such as Parkinson's disease.
•Brain tumors or cysts
•Dementia (including Alzheimer's disease)
•HIV and other infections that affect the brain
•Some types of epilepsy
•Stroke
Psychosis (or psychotic symptoms) may also be found in:
•Most people with schizophrenia
•Some people with bipolar disorder (manic-depressive) or severe depression
 Schizophrenia
• Schizophrenia is a group of psychotic disorders characterized by
disturbances in perception, affect, behavior and communication
lasting longer than 6 months (this includes psychotic behavior).
The person suffering from schizophrenia has deteriorated
occupational, interpersonal and self-supportive abilities.

Schizophrenia is
considered to be a
neurodevelopmental
disorder.
Important to Remember…
• Schizophrenic symptoms are divided into two broad
categories:
• Positive symptoms: include delusions (distorted or false
beliefs and misinterpretation of perceptions), hallucinations
(abnormal perceptions, especially auditory) and
disorganized speech.
• Negative symptoms: involve the reduction or loss of
normal functions; these symptoms include affective
flattening (decrease in the range or intensity of emotional
expression), alogia (decrease in the fluency of speech) and
avolition (a decrease in goal-oriented behavior).

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Dopamine Hypothesis…
• Schizophrenia is caused by increased and dysregulated levels
of dopamine in the brain.
• The dysregulation of dopaminergic neurtotransmission in
scheizophrenia is thought to occur at specific anatomic locations
in the brain.
1) The mesolimbic system: It is hypothesized that
mesolimbic system hyperactivity is responsible for the
positive symptoms of schizophrenia.
2) Mesocortical system: It is hypothesized that the
mesocortical system hypoactivity plays a role in the
negative symptoms of schizophrenia.

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Table 10-2. Central Dopamine Pathways © 2005 Elsevier
 Dopamine Hypothesis
Supportive evidence:
•Tight correlation between the therapeutic doses of conventional
antipsychotic drugs and their affinities for the D2 receptor.
•Indirect dopamine agonists (e.g., L -dopa, cocaine, and amphetamines)
can induce psychosis in healthy subjects and, at very low doses, provoke
psychotic symptoms in schizophrenics.

•The dopamine hypothesis has received support from postmortem shows

increased dopamine D2 receptor levels in the brains of schizophrenic
patients. However, it has been suggested that upregulation of D2 receptor
expression may be the result of adaptation to antipsychotic drug treatment
rather than a biochemical abnormality intrinsic to schizophrenia. In fact,
some PET studies show no significant difference in D2 receptors densities
between neuroleptic-naive schizophrenics and healthy controls.

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 Perfect so far…BUT!
The fact that several of the atypical antipsychotic drugs have
much less effect on D 2 receptors and yet are effective in
schizophrenia has redirected attention to the
role of other dopamine receptors and to nondopamine
receptors. Serotonin receptors— particularly the 5-HT 2A -
receptor subtype—may mediate synergistic effects or protect
against the extrapyramidal consequences of D 2 antagonism.

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 THE SEROTONIN HYPOTHESIS
• Indole hallucinogens such as LSD (lysergic acid diethylamide) and
mescaline are serotonin (5-HT) agonists.
• The discovery that 5-HT 2A -receptor and possibly 5-HT 2C
Stimulation was the basis for the hallucinatory effects of these agents
• It has been found that 5-HT 2A -receptor blockade is a key
factor in the mechanism of action of the main class of atypical
antipsychotic drugs, of which clozapine is the prototype, and
Includes melperone, risperidone, zotepine, blonanseine olanzapine,
quetiapine, ziprasidone, aripiprazole, sertindole, paliperidone,
iloperidone, asenapine, and lurasidone. These drugs are inverse
agonists of the 5-HT 2A receptor.

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 THE SEROTONIN HYPOTHESIS
• 5-HT 2A receptors modulate the release of dopamine, norepinephrine,
glutamate, GABA and acetylcholine, among other neurotransmiters in
the cortex, limbic region, and striatum. Stimulation of 5-HT 2A
receptors leads to depolarization of glutamate neurons, but also
stabilization of NMDA receptors on postsynaptic neurons. Recently, it
has been found that hallucinogens can modulate the stability of a
complex consisting of 5-HT 2A and NMDA receptors.

• Stimulation of 5-HT2C receptors leads to inhibition of cortical and

limbic dopamine release. Many atypical antipsychotic drugs, eg,
clozapine, asenapine, olanzapine are 5-HT2C inverse agonists. 5-HT
2C agonists are currently being studied as antipsychotic agents.

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 THE Glutamate HYPOTHESIS
• Hencyclidine and ketamine are noncompetitive inhibitors of the
NMDA receptor that exacerbate both cognitive impairment and
psychosis in patients with schizophrenia.
• Hypofunction of NMDA receptors, located on GABAergic
interneurons, leading to diminished inhibitory influences on
neuronal function, contributed to schizophrenia.
• The NMDA receptor, an ion channel, requires glycine for full
activation. It has been suggested that in patients with
schizophrenia, the glycine site of the NMDA receptor is not fully
saturated. There have been several trials of high doses of
glycine to promote glutamatergic activity, but the results are far
from convincing.

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Antipsychotic drugs…
• Drugs used in the management of psychosis are
often called neuroleptics or antipsychotics .
• The antipsychotics may be further divided into
typical antipsychotics , older drugs with
prominent actions at the D2 receptor, and
atypical anti-psychotics , a newer generation of
drugs with less prominent D2 antagonism and
consequently fewer extrapyramidal effects.

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 ANTIPSYCHOTIC DRUGS
A. Classification
•The major chemical subgroups of older antipsychotic drugs are the
phenothiazines (eg, chlorpromazine, thioridazine, fluphenazine) ,
the thioxanthenes (eg, thiothixene), and the butyrophenones (eg,
haloperidol).

•Newer "second generation" drugs of varied heterocyclic structure

are also effective in schizophrenia, including clozapine, loxapine,
olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole.
•In some cases, these atypical antipsychotic drugs may be somewhat
more effective and less toxic than the older drugs. However, they are
much more costly than standard older drugs, most of which are
prescribed generically.

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© 2005 Elsevier
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Figure 29–
1.

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Figure 29–2.

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 ANTIPSYCHOTIC DRUGS
Pharmacokinetics
•The antipsychotic drugs are well absorbed when given
orally, and because they are lipid soluble, they readily
enter the central nervous system (CNS) and most other
body tissues. Many are bound extensively to plasma
proteins. These drugs require metabolism by liver enzymes
before elimination and have long plasma half-lives that
permit once-daily dosing.
•In some cases, other drugs that inhibit cytochrome P450
enzymes can prolong the half-lives of antipsychotic agents.
Parenteral forms of many agents (eg, fluphenazine,
haloperidol) are available for both rapid initiation of
therapy and depot treatment.

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Mechanism of Action…typical antipsychotics
• Although the typical antipsychotics block D2 receptors in all of the CNS
dopaminergic pathways, their mechanism of action as antipsychotics
appears to involve antagonism of mesolimbic, and possibly mesocortical, D2
receptors.
• One hypothesis holds that the positive symptoms of schizophrenia correlate
with hyperactivity of the mesolimbic system, and antagonism of mesolimbic
dopamine receptors could alleviate these symptoms.
• The typical antipsychotics are relatively less effective at controlling the
negative symptoms of schizophrenia. This could relate to the hypothesis that
the negative symptoms correlate with hypoactivity of mesocortical neurons,
because the antagonist action of the antipsychotics would not be expected
to correct dopaminergic hypoactivity. Many of the adverse effects of the
typical antipsychotics are likely mediated by binding of these drugs to D2
receptors in the basal ganglia (nigrostriatal pathway) and pituitary gland.

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 Mechanism of Action
The dopamine hypothesis-
The dopamine hypothesis of schizophrenia is
not fully satisfactory because antipsychotic
drugs are only partly effective in most
patients and because many effective drugs
have a much higher affinity for other
receptors, including serotonin receptors,
than for D2 receptors.

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 Mechanism of Action

Dopamine receptors-
• Five different dopamine receptors (D1-D5) have been characterized.
Each is G-protein coupled and contains 7 transmembrane domains.
The D2 receptor, found in the caudate putamen, nucleus accumbens,
cerebral cortex, and hypothalamus, is negatively coupled to
adenylyl cyclase.
• The therapeutic efficacy of the older antipsychotic drugs correlates
with their relative affinity for the D2 receptor. Unfortunately, there is
also a correlation between blockade of D2 receptors and
extrapyramidal dysfunction.

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Figure 29–3.

Correlations between the

therapeutic potency of
antipsychotic drugs and their
affinity for binding to dopamine
D 1 ( top ) or D 2 receptors
( bottom ). Potency is indicated on
the horizontal
axes; it decreases to the right.
Binding affinity for D 1 receptors was
measured by displacing the selective
D 1 ligand SCH
23390; affinity for D 2 receptors was
similarly measured by displacing
the selective D 2 ligand haloperidol.
Binding affinity decreases upward.

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Atypical Antipsychotic Agents
• Atypical antipsychotics have efficacy and adverse
effect profiles that differ from those of the typical
antipsychotics.
• These drugs are more effective than the typical
antipsychotics at treating the “negative” symptoms
of schizophrenia.
• Atypical antipsychotics cause significantly milder
extrapyramidal symptoms than typical
antipsychotics.

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• The atypical antipsychotics have a relatively low affinity for D2
receptors; unlike the typical antipsychotics, their affinity for D2
receptors does not correlate with their clinically effective dose.
• Three main hypotheses have emerged to explain this
discrepancy:
1)The 5-HT 2 hypothesis states that antagonist action at the
serotonin 5-HT 2 receptor, or antagonist action at both 5-HT 2
and D2 receptors, is critical for the antipsychotic effect of the
atypical antipsychotics.
2)The D4 hypothesis, is based on the finding that many of the
atypical antipsychotics are also dopamine D4 receptor an-
tagonists. But the D4 hypothesis cannot account for the
mechanism of action of all atypical antipsychotics.
3)The final hypothesis states that the atypical antipsychotics
exhibit a milder adverse effect profile because of their
relatively rapid dissociation from the D2 receptor.
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 Differences among Antipsychotic Drugs
A summary of the relative receptor-binding affinities of several key agents in
such comparisons illustrates the difficulty in drawing simple conclusions
from such experiments:
•Chlorpromazine: α 1 = 5-HT 2A > D 2 > D 1
•Haloperidol: D 2 > α 1 > D 4 > 5-HT 2A > D 1 > H 1
•Clozapine: D 4 = α 1 > 5-HT 2A > D 2 = D 1
•Olanzapine: 5-HT 2A > H 1 > D 4 > D 2 > α 1 > D 1
•Aripiprazole: D 2 = 5-HT 2A > D 4 > α 1 = H 1 >> D 1
•Quetiapine: H 1 > α 1 > M 1,3 > D 2 > 5-HT 2A
Thus, most of the atypical and some typical antipsychotic agents are at least
as potent in inhibiting 5-HT 2 receptors as they are in inhibiting D 2
receptors.
Ziprasidone is an antagonist at the D2, 5-HT2A and 5-HT1D receptors and an
agonist at the 5-HT1A receptor.
Aripiprazole is a partial agonist at D2 and 5-HT1A receptors but is a strong
antagonist at 5-HT2A receptors.

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Table 29-2.

Abnormal
electrocardiograms have
been recorded,
especially with
thioridazine. Changes
include prolongation of QT
interval and abnormal
configurations of the ST
segment and T waves.
These changes are readily
reversed by withdrawing
the drug. Thioridazine,
however, is not associated
with increased risk of
torsades more than other
typical antipsychotics,
whereas haloperidol,
which does not increase
QT c , is.

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Table 29-1.

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 E. Clinical Use
1. Treatment of schizophrenia-
• Antipsychotic drugs reduce some of the positive symptoms of
schizophrenia, including hyperactivity, hallucinations, and delusions.
• Consequently, they can facilitate functioning in both inpatient and
outpatient environments. Beneficial effects may take several weeks to
develop. Overall efficacy of the antipsychotic drugs is, for the most part,
equivalent in terms of the management of the floridly psychotic forms of
the illness, although individual patients may respond best to a specific
drug.
• However, clozapine is effective in some schizophrenic patients resistant
to treatment with other antipsychotic drugs. Older drugs are still
commonly used partly because of their low cost compared with newer
agents.
• However, none of the traditional drugs has much effect on negative
symptoms of schizophrenia. Newer atypical drugs are reported to
improve some of the negative symptoms of schizophrenia, including
emotional blunting, social withdrawal, and lack of motivation.

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 E. Clinical Use
2. Other psychiatric and neurologic indications-The newer
antipsychotic drugs are often used with lithium in the initial
treatment of mania. Several second-generation drugs are approved
for treatment of acute mania; two of these (aripiprazole and
olanzapine) are approved for maintenance treatment of bipolar
disorder. The antipsychotic drugs are also used in the management
of psychotic symptoms of schizoaffective disorders, in Gilles de la
Tourette syndrome, and for management of toxic psychoses
caused by over dosage of certain CNS stimulants. Molindone is
used mainly in Tourette's syndrome; it is rarely used in
schizophrenia. The newer atypical anti psychotics have also been
used to allay psychotic symptoms in patients with Alzheimer's
disease and in parkinsonism.
3. Nonpsychiatric indications- With the exception of thioridazine,
most phenothiazines have antiemetic actions; prochlorperazine is
ptomoted solely for this indication. H1-receptor blockade, most often
present in short side-chain phenothiazines, provides the basis for
their use as antipruritics and sedatives and contributes to their
antiemetic effects.

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Table 29-3.

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Table 29-4.

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 Adverse Reactions.. A. Behavioral Effects
• The older typical antipsychotic drugs are unpleasant to take.
• A “pseudodepression” that may be due to drug-induced
akinesia usually responds to treatment with antiparkinsonism
drugs.
• Other pseudodepressions may be due to higher doses than
needed in a partially remitted patient, in which case
decreasing the dose may relieve the symptoms.
• Toxic-confusional states may occur with very high doses
of drugs that have prominent antimuscarinic actions.

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 Adverse Reactions.. B. Neurologic Effects
Extrapyramidal reactions occurring early during treatment with
older agents include typical Parkinson’s syndrome, akathisia
(uncontrollable restlessness), and acute dystonic reactions
(spasmodic or sustained involuntary muscle contractions resulting in
twisting, repetitive movements or abnormal postures.).
Parkinsonism can be treated, when necessary, with conventional
antiparkinsonism drugs of the antimuscarinic type or, in rare cases,
with amantadine. (Levodopa should never be used in these patients.).
Akathisia and dystonic reactions also respond to such treatment, but
many clinicians prefer to use a sedative antihistamine with
anticholinergic properties, eg, diphenhydramine, which can be given
either parenterally or orally.

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 Adverse Reactions.. B. Neurologic Effects
• Tardive dyskinesia, which is
characterized by a late
involuntary movements of the
face, tongue or extremities and
it may be irreversible.
• Tardive dyskinesias tend to
develop after several years of
antipsychotic drug therapy but
have appeared as early as 6
mo.

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 Adverse Reactions.. B. Neurologic Effects
• Antimuscarinic drugs that usually ameliorate other
extrapyramidal effects generally increase the severity of
tardive dyskinesia symptoms. There is no effective drug
treatment for tardive dyskinesia. Switching to quetiapine or
clozapine that do not exacerbate the condition.

• Tardive dyskinesia may be attenuated temporarily by

increasing neuroleptic dosage; this suggests that tardive
dyskinesia may be caused by dopamine receptor
sensitization.

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Adverse effects….C. Autonomic Nervous System Effects

• Most patients are able to tolerate the antimuscarinic

adverse effects of antipsychotic drugs.
• Those who are made too uncomfortable or who develop
urinary retention or other severe symptoms can be
switched to an agent without significant antimuscarinic
action.
• Orthostatic hypotension or impaired ejaculation should be
managed by switching to drugs with less marked
adrenoceptor-blocking actions.

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Adverse effects….D. Metabolic and Endocrine Effects

• Weight gain: especially with clozapine and olanzapine.

• Hyperglycemia: whether secondary to weight gain-associated
insulin resistance or to other potential mechanisms remains to
be clarified. Amenorhhea: is the absence of a menstrual period in a woman
of reproductive age.
• Hyperlipidemia may occur.
Galactorrhea: is the spontaneous flow of milk from the breast
• Hyperprolactinemia (prominent with risperidone) in women:
results in the amenorrhea-galactorrhea syndrome and infertility;
in men, loss of libido, impotence, and infertility may result.
Hyperprolactinemia may cause osteoporosis, particularly in
women.
• Aripiprazole and ziprasidone have little or no tendency to
cause hyperglycemia, hyperprolactinemia, or weight gain.

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Adverse effects….E. Toxic or Allergic Reactions
• Agranulocytosis, cholestatic jaundice, and
skin eruptions.
• Clozapine causes agranulocytosis in a small
but significant number of patients. This
serious, potentially fatal effect can develop
rapidly, usually between the 6th and 18th
weeks of therapy. It is not known whether it
represents an immune reaction, but it
appears to be reversible upon
discontinuance of the drug.

Because of the risk of agranulocytosis, patients receiving

clozapine must have weekly blood counts for the first 6
months of treatment and every 3 weeks thereafter.

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 Adverse effects…. F. Ocular Complications
• Deposits in the anterior portions of the eye (cornea and lens)
are a common complication of chlorpromazine therapy.
• Thioridazine is the only antipsychotic drug that causes retinal
deposits, which in advanced cases may resemble retinitis
pigmentosa. The maximum daily dose of thioridazine has
been limited to 800 mg/d to reduce the possibility of this
complication.

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 Adverse effects…. G. Cardiac Toxicity
• Thioridazine in doses exceeding 300 mg daily is almost always
associated with minor abnormalities of T waves that are easily
reversible.
• Overdoses of thioridazine are associated with major
ventricular arrhythmias and sudden death; it is not certain whether thioridazine can
cause these same disorders when used in therapeutic doses.
• Among the atypical agents, ziprasidone
carries the greatest risk of QT prolongation
and therefore should not be combined with
other drugs that prolong the QT interval.
• Clozapine is sometimes associated with
myocarditis and must be discontinued if
myocarditis manifests.

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Adverse effects…. I. Neuroleptic Malignant Syndrome

• Patients who are particularly sensitive to the extrapyramidal

effects of antipsychotic drugs may develop a malignant
hyperthermic syndrome. The symptoms include muscle
rigidity, impairment of sweating, hyperpyrexia, and
autonomic instability, which may be life threatening.

• Muscle-type creatine kinase levels are usually elevated,

reflecting muscle damage. This syndrome is believed to
result from an excessively rapid blockade of postsynaptic
dopamine receptors.

• Drug treatment involves the prompt use of dantrolene,

diazepam, and dopamine agonists.

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Adverse effects…. J. Sedation

• This is more marked with phenothiazines

(especially chlorpromazine) than with other
antipsychotics; this effect is usually perceived
as unpleasant by nonpsychotic persons.

• Fluphenazine and haloperidol are the least

sedating of the older drugs; aripiprazole
appears to be the least sedating of the newer
agents.

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 Use in Pregnancy; Dysmorphogenesis
The development of ill-shaped or otherwise malformed body structures.

• Although antipsychotic drugs appear to be relatively

safe in pregnancy, a small increase in teratogenic risk
could be missed.
• If a pregnant woman could manage to be free of
antipsychotic drugs during pregnancy, this would be
desirable because of their effects on the
neurotransmitters involved in neurodevelopment.

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 Overdosage toxicity
• Poisoning with antipsychotics other than
thioridazine is not usually fatal, although the FDA
has warned of an increased risk of death in elderly
patients with dementia. Hypotension often
responds to fluid replacement. Most neuroleptics
lower the convulsive threshold and may cause
seizures, which are usually managed with
diazepam or phenytoin.
• Thioridazine (and possibly ziprasidone)
overdose, because of cardiotoxicity, is more
difficult to treat.

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LITHIUM & OTHER DRUGS
USED IN BIPOLAR (MANIC-
DEPRESSIVE) DISORDER

Lithium is effective in treatment of the manic phase of bipolar

disorder and continues to be used for acute-phase illness and for
prevention of recurrent manic and depressive episodes.

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 What is Bipolar disorder?
• Bipolar affective (manic-
depressive) disorder occurs
in 1–3% of the adult
population. It may begin in
childhood, but most cases
are first diagnosed in the third
and fourth decades of life.
The manic phase: excitement, hyperactivity, impulsivity,
disinhibition, aggression, diminished need for sleep, psychotic
symptoms in some (but not all) patients, and cognitive
impairment.
Depression phase: depressed mood, diurnal variation, sleep
disturbance, anxiety, and sometimes, psychotic symptoms.
Mixed manic and depressive symptoms are also seen. Patients
with bipolar disorder are at high risk for suicide
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 A. Lithium Pharmacokinetics
• Lithium is absorbed rapidly and completely from the gut.
• The drug is distributed throughout the body water and
cleared by the kidneys at a rate one fifth that of creatinine.
• The half-life of lithium is about 20 h.
• Plasma levels should be monitored, especially during the first
weeks of therapy, to establish an effective and safe dosage
regimen. For acute symptoms, the target therapeutic plasma
concentration is 0.8-l.2 mEq/L and for maintenance 0.4-0.7
mEq/L.
– Plasma levels of the drug may be altered by changes in body
water.
– Dehydration, or treatment with thiazides, nonsteroidal anti-
inflammatory drugs (NSAIDs), angiotensin converting enzyme
inhibitors (ACEIs), and loop diuretics, may result in an increase of
lithium in the blood to toxic levels.
• Caffeine and theophylline increase the renal clearance of lithium.
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Table 29-5.

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 B. Mechanism of Action
The mechanism of action of lithium is not well defined.
* Lithium is closely related to sodium in its properties. It can substitute for
sodium in generating action potentials and in Na+ -Na+ exchange across the
membrane. It inhibits the latter process; that is, Li+ -Na+ exchange is gradually
slowed after lithium is introduced into the body. At therapeutic concentrations
(around 1 mmol/L), it does not significantly affect the Na+ -Ca2+ exchanger or the
Na+ /K+ -ATPase pump.

* Lithium inhibits several enzymes involved in the recycling of neuronal

membrane phosphoinositides. This action may result in depletion of the
second messenger source, phosphatidylinosiryl bisphosphate (PIP2), which, in
turn, would decrease generation of inositol trisphosphate (IP3) and diacylglycerol
(DAG). These second messengers are important in amine neurotransmission,
including that mediated by central adrenoceptors and muscarinic receptors.

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•One thing that is clear is that lithium
has multiple effects on second
messengers:
▴ Fine-tuning of cyclic adenosine
monophosphate (cAMP)
•Because lithium causes an
increase in baseline cAMP and a
decrease in stimulation of cAMP
formation, lithium is able to fine-
tune cAMP levels
▴ Depletion of inositol
•Inhibition of inositol
monophosphatases, leading to a
reduction in synaptic signaling
through receptors that are
coupled to phosphoinosital (PI)
turnover

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Figure 29–4.

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 B. Mechanism of Action

Another neuroprotective factor thought to mediate the

effects of lithium is the enzyme glycogen synthase
kinase 3 (GSK-3). GSK-3 regulates numerous cellular
processes such as gene transcription, synaptic plasticity,
apoptosis, and circadian rhythms, among others. Lithium's
inhibition of GSK-3 is believed to have a neuroprotective
effect.

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 B. Mechanism of Action

• Several studies suggest that lithium may uncouple

receptors from their G proteins; indeed, two of lithium’s
most common side effects, polyuria and subclinical
hypothyroidism, may be due to uncoupling of the
vasopressin and thyroid-stimulating hormone (TSH)
receptors from their G proteins.

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Inhibitory regulation of GSK-3 by lithium. Lithium negatively regulates the constitutively activated GSK-3 activity
through multiple mechanisms. Lithium, a competitive inhibitor of magnesium, directly inhibits ATP–magnesium-
dependent catalytic activity of GSK-3. The activity of GSK-3 is also reduced by phosphorylation at a specific serine
residue. Lithium can indirectly increase this serine phosphorylation of GSK-3 through PI3-kinase-mediated
phosphorylation/activation of Akt, PI3-kinase-mediated activation of PKC, and cAMP-dependent activation of
PKA. Lithium can also increase the serine phosphorylation of GSK-3 by disrupting the β-arrestin-2 (βArr2)–PP2A–
Akt complex that dephosphorylates and inactivates Akt. In addition, by disinhibiting the inhibitory action of
inhibitor-2 (I-2) on protein phosphatase-l (PP-1) that dephosphorylates GSK-3 at serine residues, lithium’s direct
inhibition of GSK-3 interrupts this auto-regulation of GSK-3 and further decreases GSK-3 activity. Lines with solid
arrows represent stimulatory connections; lines with flattened ends represent inhibitory connections. Dashed
lines represent pathways with reduced activity as a result of lithium treatment. I-2, inhibitor-2; PP-1, protein
phosphatase-l. (Modified from Chiu and Chuang, 2010).
Table 29-6.

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 Clinical Use
• Lithium carbonate continues to be used for the treatment of
bipolar disorder (manic-depressive disease) although other drugs
including valproic acid and carbamazepine are equally effective
(see text that follows). Maintenance therapy with lithium decreases
manic behavior and reduces both the frequency and the magnitude
of mood swings.
• Antipsychotic agents and/or benzodiazepines are commonly
required at the initiation of treatment because both lithium and
valproic acid have a slow onset of action.
• Olanzapine and quetiapine are both approved as mono therapy for
acute mania.
• Although lithium has protective effects against suicide and self harm
antidepressant drugs are often used concurrently during
maintenance.
• Note that mono therapy with antidepressants can precipitate mania
in bipolar patients.

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 Adverse Effects & Complications
A. Neurologic and Psychiatric Adverse Effects
•Tremor is one of the most common adverse effects of
lithium treatment, and it occurs with therapeutic doses.
Treatment: Propranolol and atenolol.
•Motor hyperactivity, ataxia, dysarthria, and aphasia.
•Psychiatric disturbances at toxic concentrations are
generally marked by mental confusion and withdrawal.
•Appearance of any new neurologic or psychiatric
symptoms or signs is a clear indication for temporarily
stopping treatment with lithium and for close monitoring of
serum levels.

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 Adverse Effects & Complications

B. Decreased Thyroid Function

•Lithium probably decreases thyroid function in most patients.

•Although initial thyroid testing followed by regular monitoring

of thyroid function has been proposed, such procedures are
not cost-effective. Obtaining a serum TSH concentration every
6–12 months, however, is prudent.

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 Adverse Effects & Complications
C. Nephrogenic Diabetes Insipidus and Other Renal Adverse
Effects
•Polydipsia and polyuria occurring at therapeutic serum concentrations.
•The principal physiologic lesion involved is loss of responsiveness to
antidiuretic hormone (nephrogenic diabetes insipidus). Lithium-induced
diabetes insipidus is resistant to vasopressin but responds to amiloride.
•Long-term lithium therapy induced kidney injury.
•Patients receiving lithium should avoid dehydration and the associated
increased concentration of lithium in urine.
•Periodic tests of renal concentrating ability should be performed to
detect changes.

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 Adverse Effects & Complications
D. Edema
•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.

http://seoanalyses.com/out2.php?k=hand%20edema

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 Adverse Effects & Complications
E. Cardiac Adverse Effects
•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.

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 Adverse Effects & Complications
F. Use During Pregnancy and lactation
•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
pregnancy may develop toxic levels after delivery.
•The use of lithium during pregnancy is thought to increase the
incidence of congenital cardiac anomalies (Ebstein's anomaly) .
Recent analyses suggest that the teratogenic risk is low, but in
pregnancy it appears to contribute to low Apgar scores in the
neonate.
– Consequently, lithium should be withheld 24-48 h before
delivery, and its use is contraindicated in nursing mothers.

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 Adverse Effects & Complications
F. Use During Pregnancy and Lactation
•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
and further research is needed in this important area.

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 Overdoses
• Therapeutic overdoses 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.
• Any value over 2 mEq/L must be considered as indicating
likely toxicity. Because lithium is a small ion, it is dialyzed
readily.

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 Other Drugs Used in Bipolar
Disorder
• The manic phase in bipolar disorder can be treated with
antipsychotic drugs, and both olanzapine and quetiapine are
approved as monotherapy for this indication.
• Several antiseizure drugs are used in bipolar disorder.
Valproic acid has anti manic effects equivalent to those of
lithium and is now widely used in the Unites States for this
indication, often as a first choice in acute illness.
• Valproic acid maybe be effective in patients who fail to
respond to lithium, and in some instances it has been used in
combination with lithium.
• The antiseizure drugs carbamazepine and lamotrigine are
also used both in acute mania and for prophylaxis in the
depressive phase.

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Skill keeper

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© The McGraw-Hill Companies, Inc., 201