DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

hygroscopic and less irritating to the gut than other
salts, especially the chloride. Since slow-release forms
carry an increased risk for polyuria, their use should be
limited to patients who experience GI side effects
related to rapid absorption.
Novel Treatments for Psychosis and Mania
There are several molecular targets for antipsychotic drug development,
including glutamate, serotonergic, and cholinergic receptor
systems. The glutamate hypofunction hypothesis for schizophrenia
has opened the door to exploration of metabotropic glutamate receptor
agonists, and agonists at co-transmitter sites. The glutamate
receptor family is divided into the excitatory ionotropic receptors,
broadly distributed in the CNS, and metabotropic glutamate receptors
that exert modulatory functions (Chapter 14). The former are
not viable targets for drug activity due to the global impact on CNS
function that may result. Metabotropic glutamate receptors show significant
promise, with agents synthesized based on the distribution
of the three receptor groups (Krivoy et al., 2008).
The mGlu 2/3 receptor agonist LY2140023 showed efficacy
in a 4-week phase 2 schizophrenia monotherapy trial (Patil et al.,
2007), and while subsequent data were problematic, similar compounds
are still in development.
Glycine is a co-transmitter at glutamate receptors whose
synaptic action is terminated by presynaptic reuptake transporters.
There are two human forms of the glycine reuptake pump:
GlyT1, which is localized to cortical areas; and GlyT2, which is
concentrated in spinal cord. The GlyT1 inhibitor SSR504734 was
as effective as haloperidol in blocking PCP-induced CNS metabolic
changes in rats. Lurasidone is a novel 5-HT/DA antagonist that filed
for FDA approval in late 2009. Lurasidone possesses potent activity
at 5-HT 7
receptor sites, actions that, based on preclinical and early
clinical studies, may be associated with cognitive benefits (Meyer
et al., 2009). Muscarinic receptor modulators at M 1
and M 4
sites
have passed several preclinical antipsychotic tests (Chan et al., 2008;
Janowsky and Davis, 2009), and xanomeline, an M 1
/M 4
agonist, has
shown antipsychotic and procognitive affects in a 4-week, doubleblind
placebo-controlled schizophrenia trial (Shekhar et al., 2008).
Certain targets (e.g., α7 and α4β2 nicotinic receptors) are being
exploited solely for the purposes of cognitive enhancement in schizophrenia,
and may not confer antipsychotic activity (Buchanan
et al., 2007).
The expanded role for atypical antipsychotics in bipolar treatment
is primarily in acute mania, although quetiapine possesses
unique effectiveness for bipolar depression based on antidepressant
properties conferred by the metabolite norquetiapine. Improved
understanding of the biological basis for Li + and anticonvulsant
actions in mania has generated several possible targets. No agents
acting on IP 3
have been developed, but several inhibitors of GSK-
3β that are 3-benzofuranyl-4-indolylmaleimide compounds have
been identified, with one showing activity in a murine mania model
(Kozikowski et al., 2007). PKC inhibition has emerged as the most
viable novel candidate for antimanic activity, based on several positive
tamoxifen trials in acute mania (Einat et al., 2007; Yildiz et al.,
2008; Zarate et al., 2007). There is still no medication that possesses
lithium’s unique broad spectrum of pharmacological activities for
bipolar disorder, and particular aspects of lithium’s actions that are
addressed in a limited fashion by current medications (e.g., lamotrigine
and quetiapine for bipolar depression), or not at all (e.g., neuroprotection),
remain important targets for novel treatments (Quiroz
et al., 2004).
Clinical Summary: Treatment of Mania
Despite decades of data substantiating the superior efficacy
of Li + in bipolar patients, including suicide reduction,
Li + remains underutilized. Long-term studies
spanning 10 or more years demonstrate that while
polyuria may be relatively common, significant
declines in renal function and renal failure are rare during
Li + treatment. Many agents are effective for acute
mania, but long-term treatment requires careful consideration
of extent and severity of prior depressive
episodes, past history of treatment response, concurrent
medical illness and medication use, patient preference,
and concerns over particular adverse effects (e.g., weight
gain). Combining mood stabilizers and antipsychotic
agents shows greater benefit for acute mania than
monotherapy of either agent class, but may be associated
with increased long-term weight gain. A realistic
discussion with patients regarding long-term side
effects for various treatments and clinical outcomes is
paramount to improve adherence. Serum level monitoring
is necessary for Li + , valproate acid compounds, and carbamazepine.
Lamotrigine may be particularly useful in
type II bipolar patients, where mania prophylaxis is not
a concern. The clinical data make a compelling argument
for Li + as the treatment of choice in bipolar I disorder.
Ongoing research into lithium’s mechanism of
action may yield new agents without lithium’s adverse
effect profile, and genetic predictors of Li + response.
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American Diabetes Association, American Psychiatric
Association, American Association of Clinical Endocrinologists,
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CHAPTER 16
PHARMACOTHERAPY OF PSYCHOSIS AND MANIA
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