PHARMACOLOGY:

PSYCHOSIS AND MANIA

Vince Edward C. Araneta, MD, DFM
Psychosis
◦ A symptom of mental illness characterized by a distorted or
non-existent sense of reality

◦ Schizophrenia has a worldwide prevalence of 1% and is

considered the prototypic disorder for understanding the
phenomenology of psychosis and the impact of antipsychotic
treatment.
Psychosis
◦ Hallucinations, delusions, disorganized speech, and disorganized or
agitated behavior comprise the types of psychotic symptoms found
individually, or rarely together, in all psychotic disorders, and are
typically responsive to pharmacotherapy.

◦ In addition to positive symptoms, schizophrenia patients also suffer

from negative symptoms (apathy, avolition, alogia), and cognitive
deficits, particularly deficits in working memory, processing speed,
social cognition, and problem solving that test 1.5-2 standard deviations
below population norms.
Schizophrenia
◦ Serotonin Hypothesis
◦ Dopamine Hypothesis
◦ Glutamate Hypothesis
Anti-Psychotics
◦ The dopamine (DA) overactivity hypothesis has led to the
development of the first therapeutic class of antipsychotic agents,
now referred to as typical or first generation antipsychotic drugs.

◦ These medications differed in potency, but shared the common

mechanism of significant DA D2 blockade and associated risk for
extrapyramidal side effects.
Psychosis Pathology and General Goals
◦ Common to all psychotic disorders are positive symptoms, which may
include hallucinatory behavior, disturbed thinking, and behavioral
dyscontrol.

◦ For many psychotic disorders the state of psychosis is transient, and

antipsychotic drugs are only administered during and shortly after
periods of symptom exacerbation.

◦ Delusional disorder, schizophrenia, and schizoaffective disorder are

chronic diseases that require long-term antipsychotic treatment.
Psychosis Pathology and General Goals
◦ For schizophrenia a schizoaffective disorder, the goat of treatment is to
maximize functional recovery by decreasing the severity of positive
symptoms and their behavioral influence

◦ Improve negative symptoms, decreasing social withdrawal, and

remediating cognitive dysfunction

◦ Treatment reduces relapse rates from 80% among unmedicated

patients to 15%
Psychosis Pathology and General Goals
◦ Regardless of underlying pathology, the immediate goal is to decrease
in acute symptoms that induce patient distress, particularly behavioral
symptoms (e.g. hostility, agitation) that may present a danger to the
patient or others.

◦ The dosing, route of administration and choice of antipsychotic depend

on the underlying disease state, clinical acuity, drug-drug interactions
with concomitant medications and patient sensitivity to short or long-
term adverse effects.
Psychosis Pathology and General Goals
◦ Avoidance of adverse effects based upon patient and drug characteristics, or
exploitation of certain medication properties (e.g., sedation related to
histamine H1 or muscarinic antagonism) are the principal determinants for
choosing initial antipsychotic therapy.

◦ All commercially available antipsychotic drugs reduce dopaminergic

neurotransmission

◦ This finding implicates D2 blockade (or, in the case of aripiprazole, modulation

of DA activity) as the primary therapeutic mechanism. Chlorpromazine and
other early low-potency typical antipsychotic agents are also profoundly
sedating, a feature that used to be considered relevant to their therapeutic
pharmacology.
Psychosis Pathology and General Goals
◦ The development of the high-potency typical antipsychotic agent
haloperidol, a drug with limited H1 and M1 affinity and significantly less
sedative effects, and the clinical efficacy of intramuscular forms of
nonsedating newer antipsychotic drugs, aripiprazole and ziprasidone,
demonstrate that sedation is not necessary for antipsychotic activity,
although at times desirable.
 Schizophrenia
◦ The immediate goals of acute antipsychotic treatment are the reduction of
agitated, disorganized, or hostile behavior, decreasing the impact of
hallucinations, the improvement of organization of thought processes, and
the reduction of social withdrawal.

◦ Doses used are often higher than those required for maintenance treatment
of stable patients.

◦ Despite considerable debate, newer atypical antipsychotic agents are not

more effective in the treatment of positive symptoms than typical agents
(Rosenheck et al., 2006; Sikich et al., 2008), although there may be small
but measurable differences in effects on negative symptoms and cognition
Schizophrenia
◦ Newer, atypical antipsychotic agents do offer a better neurological side-
effect profile than typical antipsychotic drugs.

◦ Rarely used are low-potency typical agents (e.g., chlorpromazine),

which also have high affinities for H1, M, and α1 receptors that cause
many undesirable effects (sedation, anticholinergic properties,
orthostasis)

◦ In acute psychosis, sedation may be desirable, but the use of a

sedating antipsychotic drug may interfere with a patient’s cognitive
function and social reintegration.
Schizophrenia
◦ Since schizophrenia requires long-term treatment, antipsychotic agents
with greater metabolic liabilities, especially weight gain should be
avoided as first-line therapies.

◦ Ziprasidone and aripiprazole are the most weight and metabolically

neutral atypical agents, with asenapine and iloperidone also having
favorable metabolic profiles.

◦ Ziprasidone and aripiprazole are available in IM form, thus permitting

continuation of same drug treatment initiated parenterally in the
emergency room.
Choosing the Drug
◦ Choice among antipsychotic drugs is based mainly on differences in
adverse effects and possible differences in efficacy. Since use of the
older drugs is still widespread, especially for patients treated in the
public sector, knowledge of such agents as chlorpromazine and
haloperidol remains relevant.

◦ Thus, one should be familiar with one member of each of the three
subfamilies of phenothiazines, a member of the thioxanthene and
butyrophenone group, and all of the newer compounds—clozapine,
risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole
Parenteral Preparations
◦ Well-tolerated parenteral forms of the high-potency older drugs
haloperidol and fluphenazine are available for rapid initiation of
treatment as well as for maintenance treatment in noncompliant
patients.

◦ Since the parenterally administered drugs may have much greater

bioavailability than the oral forms, doses should be only a fraction of
what might be given orally, and the manufacturer’s literature should be
consulted.
Parenteral Preparations
◦ Fluphenazine decanoate and haloperidol decanoate are suitable for
long-term parenteral maintenance therapy in patients who cannot or will
not take oral medication.
Haloperidol
◦ Haloperidol is a typical butyrophenone type antipsychotic that exhibits
high affinity dopamine D2 receptor antagonism and slow receptor
dissociation kinetics.

◦ The drug binds preferentially to D2 and α1 receptors at low dose and 5-

HT2 receptors at a higher dose. Given that antagonism of D2 receptors
is more beneficial on the positive symptoms of schizophrenia and
antagonism of 5-HT2 receptors on the negative symptoms

◦ Haloperidol's negligible affinity for histamine H1 receptors and

muscarinic M1 acetylcholine receptors yields an antipsychotic with a
lower incidence of sedation, weight gain, and orthostatic hypotension
Adverse Effects
◦ Extrapyramidal reactions occurring early during treatment with older
agents include typical Parkinson’s syndrome, akathisia (uncontrollable
restlessness), and acute dystonic reactions (spastic retrocollis or
torticollis).

◦ Tardive dyskinesia, as the name implies, is a late-occurring syndrome

of abnormal choreoathetoid movements. It is the most important
unwanted effect of antipsychotic drugs.

◦ It has been proposed that it is caused by a relative cholinergic

deficiency secondary to supersensitivity of dopamine receptors in the
caudate-putamen.
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—common

complications of therapy with chlorpromazine or
mesoridazine—should be managed by switching to drugs
with less marked adrenoceptor-blocking actions.
Mania
◦ This is a period of elavated, expansive or irritable mood with co-existing
symptoms of increased energy and goal-directed activity.

◦ Represents one pole of what had been termed manic-depressive

illness, but is now referred as bipolar disorder.

◦ Distinguished from its less severe form, hypomania, by the fact that
hypomania, by definition, does not result in functional impairment or
hospitalization, and is not associated with psychotic symptoms.
Mania
◦ Genetic studies of bipolar disorder have yielded several loci of interest
associated with disease risk and predictors of treatment response.

◦ No medication has yet been designed to treat the full spectrum of

bipolar disorder based on performed biological hypotheses of the
illness.

◦ Lithium was introduced fortuitiously in 1949 for the treatment of mania

Basic Pharmacology of Lithium
◦ Lithium is a small monovalent cation (Pharmacokinetics)

◦ Pharmacodynamics
◦ Directly inhibits two signal transduction pathways
◦ It both suppresses inositol signaling through depletion of intracellular
inositol and inhibits glycogen synthase kinase-3 (GSK-3), a
multifunctional protein kinase.
◦ GSK-3 is a component of diverse intracellular signaling pathways.
◦ These include signaling via insulin/insulin-like growth factor, brain
derived neurotrophic factor (BDNF), and the Wnt pathway
Effects on Electrolytes and Ion Transport
◦ 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.
Effects on Second Messengers
◦ One of the best-defined effects of lithium is its action on inositol

◦ Lithium inhibits inositol monophosphatase (IMPase) and other

important enzymes in the normal recycling of membrane
phosphoinositides,

◦ This block leads to a depletion of free inositol and ultimately of

phosphatidylinositol-4,5-bisphosphate (PIP 2 ), the membrane
precursor of IP 3 and DAG.
 Effects on Second Messengers
◦ Over time, the effects of transmitters on the cell diminish in proportion to the
amount of activity in the PIP 2 -dependent pathways

◦ The activity of these pathways is postulated to be markedly increased during a

manic episode.

◦ Treatment with lithium would be expected to diminish the activity in these

circuits.
 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 percentage of bipolar
patients now receive lithium.

◦ This trend is reinforced by the slow onset of action of lithium

Clinical Pharmacology of Lithium
◦ Over-all remission rate of 80%

◦ The depressive phase requires concurrent use of anti-depressant drug

◦ TCAs have been linked to precipitation of mania where as SSRIs are

less likely to induce mania

◦ Lithium at therapeutic concentrations is devoid of autonomic blocking

effects and of activating or sedating effects, although it can produce
nausea and tremor
Drug Interactions
◦ Renal clearance is reduced by 25% by diuretics and doses may need to
be reduced by a similar amount.

◦ Similar reduction in lithium clearance has been noted with several of

the newer nonsteroidal anti-inflammatory drugs that block synthesis of
prostaglandins.

◦ All neuroleptics tested to date, with the possible exception of clozapine

and the newer atypical antipsychotics, may produce more severe
extrapyramidal syndromes when combined with lithium.
Adverse Effects and Complications
◦ Neurologic and Psychiatric Adverse Effects
- Tremor is the most common
- Choroathetosis, motor hyperactivity, ataxia, dysarthria, aphasia
- Mental confusion and withdrawal
- Appearance of any new neurologic or psychiatric symptom is an
indication for temporarily stopping treatment
 Adverse Effects and Complications
◦ Decreased Thyroid Function
- Probably decreases thyroid function but the effect is reversible
- Obtaining a serum TSH every 6-12 months however is prudent
◦ Nephrogenic Diabetes Insipidus and Other Renal Adverse Effects
- polydipsia, polyuria
- loss of responsiveness to ADH
- patients should avoid dehydration
Adverse Effects and Complications
◦ Edema
◦ Cardiac Adverse Effects
Bradycardia-tachycardia is a definite contraindication
◦ Use During Pregnancy
- patient whose serum lithium concentration is in a good
therapeutic range during pregnancy may develop toxic levels after
delivery
 Adverse Effects and Complications
◦ 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 hepatomaegaly.

◦ 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
Adverse Effects and Complications
◦ Folliculitis is less dramatic and probably occurs more frequently.
Leukocytosis is always present during lithium treatment, probably
reflecting a direct effect on leukopoiesis.
Overdoses
◦ Therapeutic overdoses of lithium are more common than those due to
deliberate or accidental ingestion of the drug.

◦ 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

◦ Because lithium is a small ion, it is dialyzed readily. Both peritoneal

dialysis and hemodialysis are effective.
Valproic Acid
◦ Has been demonstrated to have antimanic effects and is now being
widely used for this indication in the USA

◦ Overall, valproic acid shows efficacy equivalent to that of lithium during

the early weeks of treatment.

◦ 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.
Valproic Acid
◦ 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.
Carbamazepine
◦ Considered to be a reasonable alternative to lithium when the latter is
less than optimally efficacious

◦ Mode of action is unclear

◦ Adverse effects are generally no greater and sometimes less than

those associated with lithium
 Carbamazepine
◦ 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.
Carbamazepine
◦ 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 overdoses of tricyclic antidepressants.
Other Drugs
◦ 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.