Carlos A. Zarate, Jr, MD

Bipolar disorder (BP) is a chronic, debilitating illness that affects 0.4% to 4% of the US population.

 The first nosological efforts describing BP appeared in the early 2nd century ad and culminated in Kraepelin’s eloquent description of its phenomenology in his 1921 textbook on manic-depressive insanity.

 Nevertheless, the course and underlying pathophysiology of BP remain elusive.

The disorder is frequently unrecognized, misdiagnosed, and not optimally managed. Moreover, no agent has been specifically developed on the basis of an understanding of the pathophysiology of the illness or mechanism of action of effective treatments.

The current gold standard treatment for BP is lithium, whose mood-stabilizing effects are believed to occur via distinct cellular signaling pathways/targets, such as glycogen synthase kinase 3 inhibition (considered to regulate cellular apoptosis), and other potential downstream cellular mechanisms. In addition to lithium, valproate, and carbamazepine, several atypical antipsychotics (including asenapine) are FDA-approved for the treatment of acute bipolar mania (

While these drugs have certainly provided relief for many individuals with BP, significant issues with tolerability and efficacy remain. For instance, clinicians may find themselves in situations in which better-tolerated agents are less effective, and vice versa. In addition, balancing efficacy with adverse effects that affect adherence, such as sedation and weight gain, underscore the urgent need to develop novel and more effective treatments.

Findings from a meta-analysis indicate that the following agents were more effective than placebo for mania: aripiprazole, asenapine, carba­mazepine, cariprazine, haloperidol, lithium, olanzapine, paliperidone, quetiapine, risperidone, tamoxifen, valproate, and ziprasidone).

 Limited data suggest large effect sizes for carbamazepine, cariprazine, haloperidol, risperidone, and tamoxifen.

Another large meta-analysis evaluated the comparative efficacy of aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone at therapeutic doses for treatment of acute mania.

 The study concluded that antipsychotic drugs were significantly more effective than mood stabilizers; olanzapine, risperidone, and quetiapine were better tolerated than haloperidol. Risperidone, olanza­pine, and haloperidol were particularly efficacious. Most of the trials were short (typically 3 weeks), and therefore caution is needed when extrapolating the results to clinical practice. It is also important to note that because of informed consent and general enrollment issues with manic patients, more severe cases were invariably excluded.

Because strong evidence exists for the use of lithium-and to a somewhat lesser extent, lamotrigine and valproate-as a maintenance treatment for BP, antipsychotics may be increasingly used to treat the acute manic phase of the disorder and mood stabilizers (particularly lithium) may be used for long-term treatment. Nivoli and colleagues

 reviewed the major guidelines for the treatment of manic/hypomanic and mixed episodes and found that all guidelines agreed that concurrent antidepressants should be stopped during a manic/mixed episode.

Improved pharmacological strategies with pronounced and sustained effects would have an enormous impact on public health, particularly given the high mortality associated with BP. A variety of compounds are now being tested that offer mechanistically different approaches for the treatment of BP. Some of the drugs we will discuss target partic­ular pathways specific to lithium, while others focus on more novel targets, such as 

-methyl-D-aspartate (NMDA) and opiate receptors. Evidence also suggests that older agents used to treat other diseases can be “re-purposed” if they show promise in reducing manic activity.

 While the focus of these compounds is on the treatment of mania, some may also be beneficial during the depressed phase of the illness.

Tamoxifen is a protein kinase C (PKC) inhibitor and antiestrogenic drug that crosses the blood-brain barrier and is relatively well tolerated (up to 200 mg/d). Lithium is thought to regulate the PKC signaling cascade, and findings suggest that PKC activation enhances the release of dopamine, a neurotransmitter implicated in mania.

 A recent genome-wide association study also implicated diacylglycerol kinase eta (DGKH) in the pathogensis of BP; DGKH is a key protein in the lithium-sensitive phosphatidylinositol pathway and a precursor to PKC.

A number of studies evaluated the effects of adjunctive tamoxifen treatment for mania, with encouraging results. The most recent of these was a double-blind, randomized, placebo-controlled, 6-week study (N = 40) that evaluated the efficacy and safety of tamoxifen with adjunctive lithium in the treatment of acute bipolar mania.

 Combined tamoxifen/lithium therapy was superior to lithium alone for rapidly reducing manic symptoms; results were apparent as early as day 7. In that study, all psychotropic medications except benzodiazepines were discontinued at least 48 hours before randomization.

Lorazepam (1 to 2 mg/d) was stopped after the initial 10 days and was not dispensed within 8 hours of the administration of the mania rating scale. The starting dosage of tamoxifen was 20 mg twice daily (40 mg/d). Daily doses were subsequently increased by 10 mg to achieve 80 mg/d in twice-daily divided doses. This dosage of tamoxifen was well tolerated, and no clinically significant adverse effects except fatigue were observed. Despite these clinically encouraging results, long-term safety data are limited, and tamoxifen is associated with increased risk of endometrial carcinoma and uterine sarcoma.

 This selective NMDA glutamate receptor antagonist is approved for the treatment of moderate to severe Alzheimer disease. Preclinical studies found that memantine was associated with antimanic-like properties, such as decreased locomotor hyperactivity.

 
FDA-approved treatment for bipolar disorder in adults 

In an open-label, multisite, pilot study (N = 33), 20 to 50 mg/d of memantine as monotherapy was well tolerated, and patients with acute mania responded by day 21.

 The study evaluated 3 cohorts who received either 20 to 30 mg/d, 30 to 40 mg/d, or 40 to 50 mg/d, with an allowed increase or decrease of 10 mg/d based on tolerability and response. The greatest response occurred in the group that received 20 to 30 mg/d. The most frequently reported adverse effects were nausea, headache, and constipation.

Unfortunately, no randomized placebo-controlled trials to date have demonstrated the antimanic efficacy of memantine in either manic or mixed-state patients. However, it is interesting to note that a recent 8-week, double-blind, randomized, placebo-controlled, proof-of-concept trial found that memantine augmentation (20 mg/d) of lamotrigine conferred no statistically significant benefit to patients with bipolar depression. Nevertheless, post hoc results suggest that depressive symptoms did improve in these patients during initial titration (5 mg/wk) and for the first 4 weeks but that no sustained effects were evident at 8 weeks.

 Valproic acid is widely used to treat BP; however, its teratogenicity limits its use in women of childbearing potential. Valnoctamide is an analogue of valproic acid, but it does not undergo biotransformation to the corresponding free acid. It also lacks key structural groups (eg, free carboxylic groups) implicated in valproic acid’s teratogenicity. In preclinical studies, valnoctamide was markedly less teratogenic than valproic acid, with no significant changes regarding embryolethality.

 The drug has anticonvulsant properties similar to those of valproate and has been marketed as an anxiolytic and sedative in several European countries.

A recent double-blind, 5-week, add-on (with risperidone up to 6 mg/d), controlled trial (N = 32) of valnoctamide was conducted to measure its efficacy in treating mania.

 Patients were given valnoctamide 600 mg/d, increased to 1200 mg/d after 4 days, or placebo. Valnoctamide was significantly more effective than placebo across all efficacy measures beginning at week 3 through week 5. Adverse events included abnormal liver function test results (less than 3 times normal) in 1 patient; the test results normalized after the patient was switched back to valproate.

No other clinical trials with valnoctamide have been conducted to date, nor are any such trials currently pending. Nevertheless, valnoctamide may be a promising alternative to valproate for treating mania in women of childbearing age. Additional surveillance data in humans are required to make definitive claims regarding this agent.

 Opiates that primarily target μ-opiate receptors have been given in the past to patients with BP

; however, specific κ-opiate receptor (KOR) agonists have not been tested in patients with mania. In animal studies, direct activation of KORs caused depressogenic or dysphoric effects, while blockade of the same receptors produced antidepressant-like effects.

 Although no specific KOR agonist is currently approved for human use, the analgesic agent pentazocine functions as a partial KOR agonist, with weaker affinity for μ- and σ-opiate receptors.

In a recent proof-of-concept, open-label, add-on, 3-day, acute-dose study, 10 inpatients with BP-I who were hospitalized for mania received two 50-mg doses of pentazocine 2 hours apart.

 Manic symptoms were reduced 1 hour after each dose (44% after the first dose, and 41% after the second dose). Participants initially received standard treatment for BP. Efficacy measures used in the 3-day trial included the Young Mania Rating Scale (YMRS) and the Mania Acute Change Scale7-scored at hourly intervals for 6 hours.

No psychotomimetic, dysphoric, or adverse events occurred. Patients’ vital signs were stable throughout the study, and light-headedness and sedation were noted to be minimal. Limitations included the design and small number of patients in the study and questions as to whether the effects of this agent were sustained or transient. Nevertheless, these promising initial results may provide the impetus to conduct larger trials. An ongoing study is currently evaluating the effects of pentazocine versus those of lorazepam or placebo on manic symptoms.

 Kraepelin was the first to associate manic symptoms with hyperuricemia, uric acid excretion, and gout. (Machado-Vieira and colleagues

 provide a thorough review of purinergic dysfunction in mania.) Allopurinol is a xanthine oxidase inhibitor approved for the treatment of gout. Results from initial add-on studies with allopurinol in refractory mania were positive; however, sample sizes were small and allopurinol was used in conjunction with a variety of medications, including antipsychotics.

A recent 4-week, randomized, placebo-controlled, double-blind study (N = 180) evaluated the efficacy of allopurinol (600 mg/d) or dipyridamole (a nucleoside inhibitor; 200 mg/d) in combination with lithium.

 A linear model analysis found that allopurinol resulted in greater mean reductions in YMRS scores from baseline to day 21 (

 = .003) compared with placebo. Remission rates were also more favorable for persons who received allopurinol than for those who received dipyridamole or placebo (

 = .008). Furthermore, decreased plasma uric acid levels were significantly positively associated with antimanic effects in the allopur­inol group. Overall, allopurinol was well tolerated; the most common adverse effects were dizziness and di­arrhea. An ongoing clinical trial is evaluating allopurinol as a maintenance strategy for mania in BP.

 L-type calcium channels affect several organ systems and are widely expressed in the CNS, thus influencing neuroplasticity and neuronal excitability. Lithium is known to act on calcium signaling pathways, and recent genome-wide association studies support an association between a common variation on the α 1C subunit of the L-type voltage-gated calcium channel gene and BP.

In 2007, Memory Pharmaceuticals Corporation conducted a phase 2a study of MEM 1003, a novel L-type calcium channel antagonist, for acute mania in BP. Study participants (N = 84) were randomized to receive either MEM 1003 or placebo for 3 weeks. Despite positive tolerability and safety data, both primary and secondary outcome measures showed that MEM 1003 was ineffective in treating bipolar mania.

 These results, unfortunately, are in line with earlier failed studies that investigated calcium channel antagonists in the treatment of BP.

 While it is beyond the scope of this article to offer an intensive review of all agents, we do wish to briefly mention NAC, which affects the glutathione antioxidant system. In patients with BP, a subgroup analysis found that NAC led to remission of manic symptoms.

 Most studies, however, suggest that NAC has more robust effects on depressive symptoms.

 The expression “nutraceutical” was coined in 1989 and was defined as “a food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease.”

 Nutraceuticals differ from dietary supplements because they are intended to not only supplement the diet but also to prevent and/or treat a particular disease or disorder. Many patients with BP (60%) who adhere to pharmacological treatment continue to experience recurring manic or depressive mood episodes while taking medications at recommended therapeutic doses. Thus, adjunctive neutraceuticals can act as agents with either super-additive or multi-target biologic effects or as agents with the potential to minimize adverse effects by reducing the necessary dose of conventional drugs.

Note that despite active research, no substantive evidence exists to support these notions. However, Sarris and colleagues

 recently conducted a systematic review of human clinical trials of nutraceuticals used adjunctively with standard pharmacotherapy in BP. Inclusion criteria (eg, open label, controlled, sample size greater than 10) narrowed 1710 studies to 18 that evaluated ω-3, NAC, inositol, and vitamins and minerals in combination with standard medications to treat BP (either mania or depression). Several nutraceuticals were found to improve bipolar mania, including a chelated mineral formula, l-tryptophan, magnesium, folic acid, and branched-chain amino acids (eg, leucine, isoleucine, and valine).

In contrast, the evidence did not support the adjunctive use of ω-3 in bipolar mania, although it may be useful in bipolar depression. Given that many of the trials involved small sample sizes and did not account for baseline dietary patterns, these positive results should be interpreted with caution. Likewise, significant heterogeneity between studies also prevented a meta-analysis of the findings.

While challenges in treating mania persist, the future discovery of novel therapeutic agents will likely expand our understanding of this devastating illness and provide key insights into future drug development.

-The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and thank the 7SE Research Unit of the NIMH-NIH for their support.

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Articles

New Drug Developments for Bipolar Mania

Although several antimanic agents are available to treat individuals with bipolar disorder (BD), many patients have a less than satisfactory response or experience adverse effects.

 With the exception of lithium, all of the current antimanic agents are either anticonvulsant or antipsychotic drugs. It is remarkable that no drug has been developed specifically for BD, especially because this illness was conceptualized more than a century ago. The lack of available therapeutics with a novel mechanism of action results in large part from our modest understanding of the relevant molecular and cellular substrates of this complex emotional, behavioral, and activity disorder.

Different strategies have been proposed for the development of better compounds for patients with psychiatric disorders. It has been argued that the ultimate goal of drug development should be to reduce the prevalence of psychiatric disorders through cure therapeutics and strategic preventive measures. Insel and Scolnick

 have suggested that drug development for mental disorders over the past 50 years has been significantly stalled compared with other areas of medicine and that drastically different approaches are in order.

It is our firm opinion that we are entering an era in which we will be able to develop markedly improved treatments for severe mood disorders. A growing body of data suggests that mood disorders arise from abnormalities in synaptic and neuronal plasticity cascades, leading to aberrant information processing in critical synapses and circuits.

Thus, these illnesses can best be conceptualized as genetically influenced disorders of synapses and circuits rather than simply as deficits or excesses in individual neurotransmitters. In this article, we discuss current approaches to drug development in mood disorders at the Mood and Anxiety Disorders Program of the Intramural Research Program at the National Institute of Mental Health and provide an example of one such approach.




At the Mood and Anxiety Disorders Program, the model of drug development that we are pursuing is based on 2 highly integrated preclinical-clinical pathways:

1. 

Understanding the long-term, therapeutically relevant targets of the medications currently in use.

 For example, in the case of SSRIs, instead of studying the initial increases in intrasynaptic serotonin, the goal would be to study the long-term changes in synaptic and neural plasticity that likely underlie their delayed therapeutic effects. Such knowledge can then be used to design new drugs directed at the target(s).

2. 

Understanding the pathophysiology of the illness and using that knowledge to design therapeutics to attenuate or prevent pathological processes.

 These may be envisioned as true disease-modifying strategies rather than simply as symptom control.

Because of space limitations, this article focuses on the first approach. For there to be substantial progress in generating novel compounds, susceptibility genes involved in illness need to be identified. However, this alone is insufficient to provide the knowledge necessary to expand our current therapeutic armamentarium. Fundamentally, we need information about the intracellular signaling cascades that are disrupted within the complex set of interacting neuronal networks and the specific changes that occur within these systems as a result of the effective treatments administered in a therapeutically relevant paradigm and in a time sensitive manner.

For example, much could be learned by gathering information at the precise point when there is a change in mood episode poles (switch from depression to mania) in BD or when an effective treatment intervention takes place. The advent of methodologies such as subtractive hybridization, messenger RNA differential display, and microarrays has illustrated the importance of hypothesis-generating by mimicking the conditions of illness or examining when effective treatments act (eg, in an animal model of mania and lithium treatment); this is particularly true when dealing with disorders whose pathophysiology remains elusive.



Thus, it may be very useful to develop drugs that are based on pertinent intracellular signaling molecular targets of current mood stabilizers; these later could be adapted to optimize efficacy, specificity, and/or adverse-effect profiles. In addition, all current medications have a considerable onset lag before their full therapeutic properties are activated (implying changes in gene expression, protein function, and-more generally-plasticity). Thus, identification of targets after prolonged treatments in cell- and animal-based models may be a useful approach in the development of novel therapeutics.

This approach may increase the likelihood of identifying relevant downstream targets with potentially more potent and rapid actions. Ultimately, novel agents identified in this manner also may benefit patients who are treatment-resistant, because alterations in the intracellular pathways (ie, defects) could simply be bypassed to the end-stage molecular targets that are ultimately relevant to the therapeutic effects. The use of this strategy could provide clues on how to bypass the defect in a number of ways. There is no shortage of targets, and the task of determining the ones that are most therapeutically relevant is challenging.

Our work attempts to focus on those target proteins and pathways with the most evidence for involvement in mood disorders, the greatest relevance to current disease models, or where other medications with the same or similar actions have been developed and could be used for proof-of-concept trials.



An example of drug development for BD: identification of a novel molecular target


The recent identification of biochemical targets of effective treatments has been facilitated by gene and protein expression profiling, which has led to the identification of several hitherto unexpected targets. It is important to note that these methodologies are only a screening technique, and the results need independent validation. More information on understanding the molecular mechanisms presumably involved in mood stabilization through genome-wide gene expression profiling is reviewed elsewhere.

 

Because target validation for complex psychiatric disorders is so challenging, the following criteria for selecting mood stabilizers for further study were put forth: (1) corroboration of a target at the protein and functional level; (2) observation with chemically dissimilar but clinically effective agents; (3) occurrence at a dose/plasma level 

 time frame consistent with clinical therapeutic effect; (4) localization to brain regions implicated in the neurobiology of the disorder under consideration; (5) when known, relevance to pathophysiology; and (6) when possible, tethered to human genetic findings. Application of these stringent criteria led a number of independent groups

 to recognize protein kinase C (PKC) as a promising direct biochemical target for developing therapeutics to treat BD.

The mood stabilizers that meet the aforementioned criteria for further testing are lithium (a monovalent cation) and valproate (an 8-carbon, branched fatty acid). Lithium and valproate are structurally dissimilar, but researchers have postulated that their similar therapeutic effects take place in the critical circuits of brain regions implicated in the pathophysiology of BD. The therapeutic effects are specific to these agents and occur at drug concentrations in vivo. The resultant biochemical changes occur only after long-term-but not short-term-administration in a time frame consistent with improvement of symptoms of the illness.

Both lithium and valproate were found to bring about markedly analogous effects on the PKC signaling cascade, actions that appear to be most pertinent to their antimanic profile. The PKC example we will now describe is one of the few instances in which a drug is being developed specifically to treat BD based on an identified molecular target. Indeed, such development has gone from identifying a direct molecular target in 1990 to a positive, proof-of-concept clinical study with a modulator of the relevant target in humans in 2007.




PKC is a family of 12 closely and structurally related isozyme subspecies with a heterogeneous distribution throughout the body that depends on isoforms.

 In the brain, PKC has a varied distribution and plays a significant role in regulating synaptic facets of neurotransmission. A number of additional functions for PKC have been described, including regulation of neuronal excitability, neurotransmitter release, long-term alterations in gene expression and plasticity, and mediation of intracellular signaling pathways.


Biochemical data support the possible connection between PKC and the pathophysiology and treatment of BD. Friedman and colleagues

 studied PKC activity and PKC translocation in response to serotonin in platelets collected from patients with BD before and during lithium treatment. They found that the ratios of platelets membrane-bound to cyto- solic PKC activity were increased in participants during a manic episode.

 found increased PKC activity and translocation in the brains of patients with BD compared with controls.

Studies have also shown that PKC signaling pathways are altered after treatment with lithium or valproate.

 Long-term treatment with lithium in rats resulted in a significantly decreased PKC stimulation-induced release with phorbol esters in the cortex, hypothalamus, and hippocampus. PKC isozymes a and e were reduced in the frontal cortex and hippocampus following lithium administration.

 Similarly, valproate was also found to cause an isozyme-specific decrease in PKC a and e.



Furthermore, studies have shown that stimulants, such as amphetamine, which are capable of triggering manic episodes in susceptible individuals and which induce manic-like behaviors in rodents,

 activate PKC and growth-associated protein (GAP)-43 phosphorylation (implicated in neurotransmitter release).

 Given the compelling biochemical data, a number of behavioral studies have been undertaken to validate the role of PKC in mania-related behaviors. 

In rodents, the PKC inhibitor tamoxifen significantly reduced amphetamine-induced hyperactivity in a large open field without affecting spontaneous activity, and it normalized amphetamine-induced increases in visits to the center of an open field (representing risk-taking behavior); tamoxifen also attenuated amphetamine-induced phosphorylation of GAP-43.

 PKC activity is increased in the prefrontal cortex following exposure, and the ability of the prefrontal cortex to regulate emotion, thought, and action is markedly impaired by overactivity of PKC sig- naling.

 the evidence suggests that pharmacological or stress-induced activation of PKC in animals results in many of the behavioral changes seen in mania, such as hyperactivity, risk-taking behavior, and increased hedonic drive. Its inhibition attenuates these same behavioral changes in a manner similar to that of mood stabilizers on acute mania.

These data strongly suggested that further study of PKC inhibitors in humans with BD was indicated. When the decision was made to further validate this target in humans, tamoxifen was the only relatively selective PKC inhibitor available to test. Tamoxifen, a synthetic antiestrogen widely used in the treatment of breast cancer, has a favorable adverse-effect profile compared with other chemotherapeutic agents

; considerable data exist on its safety profile and ability to cross the blood-brain barrier.

Finally, the exciting recent identification of a bipolar susceptibility gene that is an upstream regulator of PKC has strengthened the potential role of PKC signaling pathway in the pathophysiology of BD. For example, 2 recent, independent genome-wide association studies identified diacylglycerol (DAG) kinase e (DGKH) as a gene associated with higher risk of BD.

 DGKH is a major regulator of DAG, which activates all known classic and novel isoforms of PKC.



PKC inhibitors: novel therapeutics for acute mania?


Based on the data generated since the 1990s, researchers embarked on proof-of-concept studies with tamoxifen for acute mania. The first study included 7 patients (5 male and 2 female) with acute bipolar mania.

 Participants were inpatients or outpatients aged 18 to 65 years with a diagnosis of bipolar mood disorder manic episode based on a 

 structured clinical interview. Tamoxifen resulted in a significant decrease in manic symptoms as rated by the Young Mania Rating Scale (YMRS), with a mean decrease of 10 points. In addition, 71% of patients met response criteria (ie, a 50% decrease in the YMRS score from baseline).

In a double-blind, placebo-controlled monotherapy pilot trial in patients with bipolar mania, tamoxifen was found to have significant antimanic effects as early as day 5 and throughout the 3 weeks of the trial.

 Very recently, these studies were replicated in a larger placebo-controlled study.

 These studies confirm the hypothesis that directly inhibiting PKC improves manic symptoms. It is important to emphasize that while these findings are encouraging, the results are preliminary and based on fairly small sample sizes; the results need to be confirmed in larger studies involving several hundred participants and with more selective PKC inhibitors.

Nonetheless, this strategy illustrates that it is possible to develop a drug to treat a specific disorder; in this case, the illness was BD, for which no novel mechanism of action had ever been identified and proved in clinical studies.

The evidence to date on multiple levels (ie, preclinical, clinical) supports further study of PKC inhibitors in BD. Other selective PKC inhibitors are currently in phases 1 through 3 of development for treatment of a variety of conditions (eg, diabetic complications) and are possible candidates to test in BD.

 Naturally, issues regarding PKC isoform selectivity, brain penetrance, and short- and long-term tolerability will need to be examined.

Finally, a point that merits further discussion is our need to integrate current technologies with the drug evaluation process in proof-of-concept studies. The importance of identifying endophenotypes in complex neuropsychiatric disorders has been reviewed elsewhere.

 Briefly, endophenotypes can be conceptualized as quantifiable components along the pathway between phenotype of disease and distal genotype. An endophenotype may be biochemical, neuropsychological, endocrinological, neuroanatomical, cognitive, or neurophysiological (eg, seen in magnetic encephalography, polysomnography) in nature. 

These new investigational tools are beyond the scope of this review. We note them, however, because they may have considerable utility in predicting phenomena such as time to response, remission, and degree of improvement. Given our current inability to predict who will respond to which medication and within what time frame, the evaluation of characteristics observed using valuable new technologies may provide a better understanding of the neurobiological basis involved in symptom improvement, and it also may allow for the identification of surrogate outcomes and molecular targets for the next generation of treatments. Indeed, such strategies are being increasingly used in our study of complex neuro-behavioral medical illnesses.




Thus, there is now strong evidence to support the view that targeting intracellular signaling cascades is a useful strategy in drug development for BD. The use of modulators of ubiquitous kinases in the CNS, however, is met with some trepidation because of possible problems in specificity, tolerability, and safety. At present, many kinases are in the early stages of drug development for diverse medical illnesses.

 It should be emphasized that while appropriate concerns regarding these compounds are in order, lithium is a drug that targets multiple signaling cascade molecules, has been found to be generally safe, and has been a primary therapeutic used for BD for more than half a century. This latter point illustrates that it may, indeed, be possible to develop safe and effective signaling system modulators for CNS illnesses.

We believe that the strategy of drug development research we have described here will, in due course, result in noticeably improved therapeutics for psychiatric illnesses.

 

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Although several antimanic agents are available to treat individuals with bipolar disorder (BD), many patients have a less than satisfactory response or experience adverse effects.1 With the exception of lithium, all of the current antimanic agents are either anticonvulsant or antipsychotic drugs. It is remarkable that no drug has been developed specifically for BD, especially because this illness was conceptualized more than a century ago.

Carlos A. Zarate, Jr, MD

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