(i.e., LTG for maintenance treatment of bipolar disorder and the extended-release formulation of CBZ for acute mania).
TABLE 10-1 MOOD STABILIZERS FOR TREATMENT OF BIPOLAR DISORDER | ||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Anticonvulsants (e.g., VPA, LTG, CBZ)
SGAs (e.g., OLZ, RISP, QTP)
Therapeutic neuromodulation (e.g., electroconvulsive therapy [ECT], vagus nerve stimulation [VNS], transcranial magnetic stimulation [TMS])
neurotransmitters such as norepinephrine (NE) or serotonin (5-HT) benefits both depression and mania, it is not surprising that the action of these drugs support the original concept. It is also recognized that receptor changes modulated by alteration in genetic expression are slower to occur, are more sustained, and may be more consistent with the time course of mood improvement. Models to further clarify the underlying pathophysiology of bipolar disorder also incorporate such factors as genetic vulnerability and cyclicity (32,33).
The classic neurotransmitters (e.g., NE, dopamine [DA] 5-HT, acetylcholine [ACh]) implicated in affective disturbances
Cellular processes involving the classic ligand-receptor interaction and beyond (e.g., G-proteins, second messenger systems)
Subsequent intracellular events (e.g., protein kinase C [PKC] activity, neurotropic effects)
The modulating interactive processes among various neurotransmitter systems, neurohormones, and genetic influences
The role of circadian rhythms
neuronal membranes. Meltzer (52) postulated a specific macromolecular complex composed of at least the sodium, potassium, and calcium pumps; the related ion channels; and ankyrin, which may be abnormally constituted in bipolar illness. Further elucidation of this hypothesis might help identify a specific membrane fault in bipolar disorder as well as more specific pharmacotherapies. For example, omega-3 fatty acids could possibly regulate mood stabilization in bipolar patients by inhibiting signal transduction mechanisms in neuronal membranes (21).
By implication, different treatments (e.g., lithium, antipsychotics, anticonvulsants) may interrupt the natural course of the illness at different phases, favorably altering its progression. Ghaemi et al. (65) postulated that interactions among second messengers, gene regulation, and synthesis of long-acting trophic factors in the context of kindling may explain how environmental stress coupled with genetic vulnerability can lead to bipolar disorder over time.
It is present in many bipolar patients, even when stable
Early life stressors and genetic predisposition are important factors
Corticotropin-releasing hormone hyperdrive, arginine/vasopressin dysregulation, and glucocorticoid receptor dysfunction are all implicated
Agents targeting this axis hold therapeutic promise
TABLE 10-2 CONCORDANCE (+) AND DISCORDANCE (-) OF MOOD DISORDER IN TWIN PAIRS | ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Schizoaffective disorder
Cyclothymic personality
Hypomania (without depression)
specific genetic heritability for bipolar illness. For example, linkage to the genetic markers of color blindness, associated with a region of the X chromosome, is reported in some, but not all, pedigrees (82). The association of bipolar disorder to chromosome 11 suggested to occur in the Amish pedigree did not replicate with a larger sample (83). A corollary to the chromosome 11 story is the nearby location of genes involved in tyrosine hydroxylase production as well as a muscarinic cholinergic receptor gene. Subsequent genetic linkage data identify bipolar susceptibility loci in multiple regions (i.e., polygenic inheritance of the human genome), including 4p16, 12q24, 13q31, 18p11.2, 18q22, 22q11, and Xq26 (84,85,86,87 and 88). Of interest, linkage studies indicate an overlap at loci 8p22, 10p14, 18p11, and 22q11 for susceptibility to both bipolar disorder and schizophrenia, suggesting shared genetic vulnerability and perhaps less distinction between these two disorders than our present diagnostic system indicates (89,90). Further, Faraone et al. (91) have also linked three regions (i.e., 12p, 14q, and 15q) with the age of onset of bipolar disorder.
Number of previous episodes
Clinical presentation (e.g., mixed states, bipolar II)
Comorbid personality disorder (e.g., borderline, narcissistic, histrionic)
Substance use disorder or alcohol abuse
TABLE 10-3 MECHANISMS OF ACTION OF EXISTING AND PUTATIVE MOOD STABILIZERS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
TABLE 10-4 PHARMACOKINETIC PROPERTIES OF STANDARD MOOD STABILIZERS | ||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Standard mood stabilizers
Lithium
Anticonvulsants (e.g., VPA, CBZ, LTG)
SGAs
Combination drug strategies
Therapeutic neuromodulation (e.g., ECT, VNS, TMS)
Treatment of an acute exacerbation of manic, hypomanic, mixed, or depressive epis-odes
Prevention of relapse after an acute episode is controlled
Prevention of future episodes
Attenuation of suicidal behavior
mania (102,103). Prophylactic efficacy is a critical consideration given the recurrent nature of this disorder. Thus, clinicians must choose the optimal strategy for acute treatment with the realization that most patients will need to continue drug therapy indefinitely. In addition, there is support for the longer-term beneficial impact of lithium on the suicide rate in bipolar patients (104,105). The authors of these reports note that the lower suicide risk associated with lithium treatment may be due to
Its mood-stabilizing properties
A lower suicide risk per se in patients who remain in treatment
A specific antisuicidal effect
TABLE 10-5 LITHIUM VERSUS PLACEBO FOR ACUTE MANIA | ||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
patients did receive antipsychotics. In 1976, Stokes et al. (112) used the same crossover design, this time assigning patients to high or low doses of lithium. Combining the data from his two studies, he was able to demonstrate a dose (and plasma level)-response relationship to remission.
grandiosity, and suspiciousness. There were no significant differences between the two drugs in the mildly active group. When schizoaffective patients and many of the severely disturbed patients who did not receive lithium for a sufficient duration were included, the antipsychotics were found to be superior.
TABLE 10-6 LITHIUM VERSUS CHLORPROMAZINE FOR ACUTE MANIA | ||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
interpretation of results. Intermediate rescue medications are often required because standard mood stabilizers are relatively slow in their onset of action. Further, if rescue medications are avoided, this usually introduces the confound of dropouts before the experimental drug can be fully effective. When feasible, a reasonable compromise is the use of modest amounts of a benzodiazepine (BZD) when necessary for a limited time (e.g., 7 to 10 days) into the active phase of treatment. This can reduce the number of nonresponding, highly agitated patients who may otherwise drop out of treatment, and in a trial of several weeks, the initial BZD effect should dissipate by the final assessments.
stabilizers for bipolar disorder is discussed in a subsequent section.
Previous paradoxical response to BZDs (i.e., behavioral disinhibition)
Known sensitivity to these agents
Acute narrow angle glaucoma
Pregnancy
sufficient to produce supranormal circulating hormone levels may induce remission of both depressive and manic symptoms in an otherwise refractory group. These results were supported by a subsequent report, suggesting that rapidcycling treatment nonresponders may benefit from the addition of levothyroxine (147). Since these are open case reports with small sample sizes, preliminary positive results need confirmation in controlled trials.
TABLE 10-7 LITHIUM LABORATORY EVALUATIONS | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
also Chapter 1). In particular, the renal and the thyroid systems require a baseline assessment and periodic reevaluation with ongoing lithium therapy.
Extensive clinical experience
Effective for euphoric mania and hypomania
Effective maintenance/prophylactic strategy
Reduces mortality rate, in part by decreasing suicidality
FDA-labeled indication
Inexpensive
Narrow therapeutic index
Slow onset of action
Numerous adverse effects
Possibly less effective for certain subtypes
High nonadherence rates
patients. Twelve subsequent open-design studies, representing 297 acutely-ill patients, found an overall moderate to marked response rate of 56%. A number of methodological problems complicate the interpretation of these results, however, including most patients were studied under nonblinded conditions. VPA was often used in combination with other psychotropics, plasma concentrations were usually not monitored, and formal diagnostic criteria derived from standard clinical ratings were typically not used. In the early European experience, the focus was on maintenance therapy of manic-depressive disease, with patients stabilized on VPA or valpromide for up to 10 years using the drug as monotherapy or in conjunction with other psychotropics. Some investigations also employed VPA in acute mania, usually in combination with antipsychotics, and reported benefit, often allowing for substantial reductions in the antipsychotic dose (150).
Panic disorder (151)
Posttraumatic stress disorder (152)
Personality disorder with aggression (153)
Dementia with agitation (154)
48% of the DVPX group (n = 69)
49% of the lithium group (n = 36)
25% of the placebo group (n = 74)
TABLE 10-8 DIVALPROEX VERSUS PLACEBO FOR ACUTE MANIAa | ||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
Allowed for lower amounts of FGA
Produced a more rapid remission of symptoms
Produced a significantly greater improvement in symptoms
Rapid antimanic onset
Can use a loading dose strategy
May be effective in certain bipolar subtypes (e.g., mixed episodes, rapid cyclers)
FDA-labeled indication
Limited long-term data
Adverse effects
Pancreatitis
Hepatoxicity
Teratogenecity
PCO; PCOS
Weight gain
Tremors
Hyperammonemia
CBZ-treated subjects had a significant increase in total cholesterol levels.
Effective against acute mania
May be useful with comorbid substance abuse
Relatively lower weight gain
May be effective for depression
FDA-labeled indication
Complex drug interactions
Adverse effects
Hyponatremia
Hematotoxicity
Stevens-Johnson syndrome (SJS)
Teratogenicity
that demonstrate mood-stabilizing properties separate and distinct from their antipsychotic effects (193,194 and 195). The lower incidence of acute EPS (and probably tardive dyskinesia) with SGAs usually favors these agents over FGAs for mood disorders. Weight and metabolic complications, however, remain an important consideration. Studies consider the SGAs from several perspectives as a treatment strategy for bipolar disorder, including
Acute monotherapy
Mania
Depression
Acute augmentation therapy
Mania
Depression
Maintenance monotherapy
Maintenance augmentation therapy
Reduction in suicidality
These receptors are implicated in the action of standard antidepressants
Most, but not all, platelet radioligand studies in medication-free patients with major depressive disorder found a significant increase in the number of binding sites of this receptor compared with control subjects
Radioligand binding studies of the postmortem brains of patients with major depressive disorder who did not receive antidepressants showed significant increases in the number of these receptors compared with both patients who had received antidepressants and normal control subjects
TABLE 10-9 SECOND-GENERATION ANTIPSYCHOTICS FOR TREATMENT OF ACUTE MANIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
improvement in the mean total YMRS score. OLZ produced a significantly greater mean improvement compared with DVPX. Response (≥50% reduction in YMRS score) and remission (end point YMRS ≤ 12) rates were
Responders: 54.4% of OLZ-treated versus 42.3% of DVPX-treated patients
Remitters: 47.2% of OLZ-treated versus 34.1% of DVPX-treated patients
TABLE 10-10 SECOND-GENERATION ANTIPSYCHOTICS VERSUS PLACEBO FOR ACUTE MANIA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
trial may be due to
A more aggressive loading dose of DVPX with higher plasma levels overall
Lower mean dose of OLZ
A longer duration of treatment
Smaller sample size
The BPRS (lithium 28.2; OLZ 28.0; p = 0.44)
The Clinical Global Impression-Improvement (CGI-I; lithium 2.75, OLZ 2.36; p = 0.163)
The MRS (lithium 13.2, OLZ 10.2; p = 0.32)
Significant adverse effects with OLZ versus placebo included an increase in weight and fasting blood glucose.
![](https://freepngimg.com/download/social_media/63059-media-icons-telegram-twitter-blog-computer-social.png)
Stay updated, free articles. Join our Telegram channel
![](https://clinicalpub.com/wp-content/uploads/2023/09/256.png)
Full access? Get Clinical Tree
![](https://videdental.com/wp-content/uploads/2023/09/appstore.png)
![](https://videdental.com/wp-content/uploads/2023/09/google-play.png)
![](https://clinicalpub.com/wp-content/uploads/2023/09/banner1.png)