from a man with chest pain, MI ruled out,

beaten down story of futility and resilience.

And I will say, “I am sorry for your loss,”

Articles

I'm reviewing a left ventriculography from a man with chest pain, MI ruled out, his wife dead for a post-crash hour...

Takotsubo Cardiomyopathy

In the past 12 months, there has been substantial progress in our understanding of molecular processes related to the pathogenesis of major psychiatric and substance use disorders, and impressive translation of this knowledge toward developing better treatment. For example, our basic understanding of brain glutamate systems has yielded tremendous advances. Glutamate is the major excitatory neurotransmitter in the brain.

 It is involved in the neuro-circuitry of memory, emotions, and cognition and is implicated in myriad psychiatric conditions, including depression, anxiety, schizophrenia, drug addiction, and neuropsychiatric disorders.

This article reviews the recent knowledge about glutamate in different psychiatric conditions based on research published in the past year.

Stress is an important risk factor in the genesis of anxiety disorder. Animal studies have shown that stress precipitates glutamate release in limbic regions that may in part act to stimulate the hypothalamus-pituitary-adrenal axis and contribute to glucocorticoid-induced neurotoxicity.

 Recent studies have found dendritic remodeling, synaptic spine reductions, glial loss, and possibly volumetric reductions from glutamate excess following stress.

 Therefore, new drugs that target glutamatergic neurotransmission may be promising candidates for pharmacological treatments for patients who have stress-related anxiety disorders.

Work by Riaza Bermudo-Soriano and colleagues

-methyl-D-aspartate receptor (NMDA-R) antagonists (memantine), NMDA-R partial agonists (D-cycloserine), and metabotropic glutamate receptors 2 and 3 (mGluR2/3) allosteric modulators (LY354740 and LY544344) may be candidates for the treatment of anxiety disorders. In preliminary human studies, presynaptic autoreceptor mGluR2/3 agonists seem to be associated with clinical efficacy.

The monoamine hypothesis for mood disorders has been the dominant model since the 1960s.

 This has been challenged because monoamine antidepressants are only effective in 50% to 60% of depressed patients, and only about 70% respond after 4 acute treatment steps based on STAR*D algorithms.

 There is now evidence that glutamate dysfunction is involved in the limbic and prefrontal circuits of depressed individuals. For example, there is an increase of extracellular glutamate during acute and chronic stress and during depression.

Animal and human studies have indicated that targeting the glutamate system may hasten onset of action of antidepressant treatment.

 There is a growing interest in ketamine-a nonselective NMDA-R antagonist. Subanesthetic doses appear to enhance the strength of cortical synapses through NMDA-R– and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-dependent and neurotrophic mechanisms and may rapidly reverse prefrontal cortex–based deficits in depression at the neurocircuitry level. The result may be the amelioration of clinical symptoms.

 replicated their previous finding that patients with bipolar depression who received a single ketamine infusion experienced a rapid and robust antidepressant response and a rapid diminution in suicidal ideation. Limitations included a small sample (N = 15) and short duration (2 weeks); also, improvement remained significant over placebo for only 3 days.

 concluded that for depressive symptoms in treatment-resistant depression, ketamine produced rapid reductions in depressive symptoms and had a relatively benign adverse-effect profile. However, the sustainability effect remains unknown. Testing the safety and tolerability of repeated-dose ketamine remains a high priority of future investigations.

The mesocorticolimbic dopamine system is central to our understanding of addiction. Nonetheless, glutamate is also of interest because it modulates dopamine activity and is involved in the development and maintenance of drug dependence, particularly in reinstatement to drug-seeking behavior.

 Decreasing glutamatergic transmission by modulation of glutamate receptors may be effective in attenuating the reinforcing effects of drugs of abuse and in preventing reinstatement to drug-seeking behavior.

-acetylcysteine (NAC), a glutamate modulator that acts on the glutamate/cysteine exchanger, on cocaine seeking in the early and late stages of the acquisition and maintenance of cocaine self-administration in rats. NAC dose-dependently decreased the propensity to seek cocaine but had no effect on the reinforcing properties of cocaine. The researchers suggest that NAC can decrease the tendency to relapse and may also help break drug cue–elicited cocaine-seeking habits.

It is interesting to note that NAC was effective in decreasing marijuana use during an 8-week, double-blind, randomized, placebo-controlled trial for treatment-seeking cannabis-dependent adolescents.

 NAC was well tolerated and associated with minimal adverse effects. In contrast, a controlled clinical trial failed to demonstrate an ability of D-cycloserine to boost relapse prevention outcomes when combined with cognitive-behavioral therapy.

 Thus, pharmacological modulation of the glutamate system may prove to be useful in the control of a range of compulsive behaviors.

The finding that noncompetitive NMDA-R antagonists such as phencyclidine and ketamine can elicit the positive, negative, and cognitive symptoms of schizophrenia in healthy individuals gave rise to the hypothesis of impaired NMDA-R functioning in psychosis. A number of compounds licensed for medical conditions, including several NMDA-R and mGluR agents, may have antipsychotic effects, but none has proved overall benefit over risks (adverse effect, tolerability).

The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST) found no beneficial effect of glycine as an add-on treatment in chronic schizophrenia. Nonetheless, given a clear role for glutamate in the neurobiology of psychosis, it remains an active target for drug development.

One of the most promising therapeutic strategies for treatment-induced dyskinesias in Parkinson disease (PD) is mGluR5 antagonism.

 found an antidyskinetic effect of mGluR5 antagonism in de novo l-dopa–treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. Glutamate dysregulation may also be involved in fragile X syndrome (FXS). The FXS mental retardation gene (Fmr1) encodes fragile X mental retardation protein (FMRP), which alters the cascade-regulating glutamate homeostasis in the brain.

In early clinical trials, mGluR5 antagonists have shown evidence of efficacy in treating neurobehavioral symptoms associated with FXS.

 Moreover, acute treatment with mGlu5 inhibitor in the Fmr1 knockout mouse suggests that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype.

 This glutamate-based therapeutic strategy may have important implications for management of such neuropsychiatric disorders as PD and FXS in the future.

Might targeting glutamate lead to new approved treatments in psychiatry? Understanding the pathophysiology of glutamate systems has yielded tremendous progress, which we hope will translate into novel and exciting neurotherapeutics. Increasing our understanding of biological vulnerability factors such as glutamate function in psychiatric disorders is important, but such advances should be combined with psychosocial interventions to yield optimal outcomes. The future is bright for developing neurotherapeutics based on the brain glutamate systems-so, up, up and away!

Sanacora G, Treccani G, Popoli M. Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. 

Moghaddam B. Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol Psychiatry. 2002;51:775-787.

 Riaza Bermudo-Soriano C, Perez-Rodriguez MM, Vaquero-Lorenzo C, Baca-Garcia E. New perspectives in glutamate and anxiety. 

 Harvey BH, Shahid M. Metabotropic and ionotropic glutamate receptors as neurobiological targets in anxiety and stress-related disorders: focus on pharmacology and preclinical translational models.

 Schildkraut JJ. The catecholamine hypothesis of affective disorders: a review of supporting evidence. 

 Gaynes BN, Rush AJ, Trivedi MH, et al. The STAR*D study: treating depression in the real world. 

 Zarate CA Jr, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. 

 Covvey JR, Crawford AN, Lowe DK. Intravenous ketamine for treatment-resistant major depressive disorder. 

 Mathew SJ, Shah A, Lapidus K, et al. Ketamine for treatment-resistant unipolar depression: current evidence. 

Wise RA, Morales M. A ventral tegmental CRF-glutamate-dopamine interaction in addiction. 

 Olive MF, Cleva RM, Kalivas PW, Malcolm RJ. Glutamatergic medications for the treatment of drug and behavioral addictions. 

Murray JE, Everitt BJ, Belin D. N-Acetylcysteine reduces early- and late-stage cocaine seeking without affecting cocaine taking in rats. 

 Gray KM, Carpenter MJ, Baker NL, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents [published correction appears in Am J Psychiatry. 2012;169:869]. 

 Kennedy AP, Gross RE, Whitfield N, et al. A controlled trial of the adjunct use of D-cycloserine to facilitate cognitive behavioral therapy outcomes in a cocaine-dependent population. 

 Sendt KV, Giaroli G, Tracy DK. Beyond dopamine: glutamate as a target for future antipsychotics. 

http://www.isrn.com/journals/pharmacology/2012/427267

 Kantrowitz J, Javitt DC. Glutamatergic transmission in schizophrenia: from basic research to clinical practice. 

Cleva RM, Olive MF. Positive allosteric modulators of type 5 metabotropic glutamate receptors (mGluR5) and their therapeutic potential for the treatment of CNS disorders. 

 Morin N, GrÃ©goire L, Morissette M, et al. MPEP, an mGlu5 receptor antagonist, reduces the development of l-DOPA-induced motor complications in de novo parkinsonian monkeys: biochemical correlates. 

 Krueger DD, Bear MF. Toward fulfilling the promise of molecular medicine in fragile X syndrome.

, Sidorov M, Ballard TM, et al. Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice. 

Glutamate and Psychiatry in 2012-Up, Up and Away!

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.

 Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication [published correction appears in Arch Gen Psychiatry. 2005;62:709]. 

 Merikangas KR, Jin R, He JP, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. 

 Mondimore FM. Kraepelin and manic-depressive insanity: an historical perspective. 

 Yildiz A, Vieta E, Leucht S, Baldessarini RJ. Efficacy of antimanic treatments: meta-analysis of randomized, controlled trials. 

 Cipriani A, Barbui C, Salanti G, et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments meta-analysis. 

 Nivoli AM, Murru A, Goikolea JM, et al. New treatment guidelines for acute bipolar mania: a critical review. 

 Ekins S, Williams AJ. Finding promiscuous old drugs for new uses. 

 DiazGranados N, Zarate CA Jr. A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. 

 Baum AE, Akula N, Cabanero M, et al. A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. 

 Amrollahi Z, Rezaei F, Salehi B, et al. Double-blind, randomized, placebo-controlled 6-week study on the efficacy and safety of the tamoxifen adjunctive to lithium in acute bipolar mania. 

 Gao Y, Payne RS, Schurr A, et al. Memantine reduces mania-like symptoms in animal models.

 Keck PE Jr, Hsu HA, Papadakis K, Russo J Jr. Memantine efficacy and safety in patients with acute mania associated with bipolar I disorder: a pilot evaluation. 

 Anand A, Gunn AD, Barkay G, et al. Early anti­depressant effect of memantine during augmentation of lamotrigine inadequate response in bipolar depression: a double-blind, randomized, placebo-controlled trial. 

 Radatz M, Ehlers K, Yagen B, et al. Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid. 

 Bersudsky Y, Applebaum J, Gaiduk Y, et al. Valnoctamide as a valproate substitute with low teratogenic potential in mania: a double-blind, controlled, add-on clinical trial. 

 Maremmani I, Perugi G, Pacini M, Akiskal HS. Toward a unitary perspective on the bipolar spectrum and substance abuse: opiate addiction as a paradigm. 

 Carlezon WA Jr, BÃ©guin C, DiNieri JA, et al. Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats. 

 Corbett AD, Henderson G, McKnight AT, Paterson SJ. 75 years of opioid research: the exciting but vain quest for the Holy Grail. 

 Cohen BM, Murphy B. The effects of pentazocine, a kappa agonist, in patients with mania. 

 ClinicalTrials.gov. Effects of pentazocine versus lorazepam or placebo on manic symptoms. 

http://clinicaltrials.gov/ct2/show/NCT00431184?term=pentazocine&rank=1)

 Machado-Vieira R, Lara DR, Souza DO, Kapczinski F. Purinergic dysfunction in mania: an integrative model. 

 Akhondzadeh S, Milajerdi MR, Amini H, Tehrani-Doost M. Allopurinol as an adjunct to lithium and haloperidol for treatment of patients with acute mania: a double-blind, randomized, placebo-controlled trial. 

 Machado-Vieira R, Lara DR, Souza DO, Kapczinski F. Therapeutic efficacy of allopurinol in mania associated with hyperuricemia.

 Machado-Vieira R, Soares JC, Lara DR, et al. A double-blind, randomized, placebo-controlled 4-week study on the efficacy and safety of the purinergic agents allopurinol and dipyridamole adjunctive to lithium in acute bipolar mania. 

New Drug Developments for Bipolar Mania

Deep brain stimulation (DBS), used in treating Parkinson disease and other movement disorders, has emerged as a promising approach for early Alzheimer disease and for treatment-resistant depression (TRD), according to recent journal articles and key researchers in the neuromodulation field.

The evolution of DBS for various neuropsychiatric disorders results from advances in structural and functional brain imaging, increased understand-ing of neurocircuitry of the brain, and improvements in neurosurgical techniques and equipment, explained Helen Mayberg, MD, Dorothy C. Fuqua Chair of Psychiatric Neuroimaging and Therapeutics at Emory University School of Medicine, who conducts depression-related DBS research.

As early as 1997, the FDA approved DBS for treatment of essential tremor; this was followed in 2002 by approval for use in advanced Parkinson disease and, in 2003, for dystonia. To date, more than 85,000 patients worldwide have had DBS devices implanted.

In a recent editorial, Andres Lozano, MD, PhD,

 RR Tasker Chair in Functional Neurosurgery at the University Health Network (UHN) in Toronto, wrote that beyond DBS’s “striking clinical benefits” for movement disorders, it may have potential for patients with non-motor neurological and psychiatric disorders.

In 2009, the FDA approved a humanitarian device exemption for DBS therapy (Medtronics’ Reclaim) to suppress the symptoms associated with chronic, severe obsessive-compulsive disorder, said Mayberg.

Possible FDA consideration of DBS for Alzheimer disease and for TRD must await the results of stimulation versus sham trials, said Peter Giacobbe, MD, Assistant Professor at the University of Toronto and Staff Psychiatrist at UHN, where he serves as Head of the ECT service. He also programs DBS devices and provides preoperative and postoperative psychiatric management of patients receiving DBS.

According to a search of open studies listed on 

 and a review article, DBS also is being studied for bipolar disorder, PTSD following combat, obesity, anorexia, addiction, Tourette syn-drome, and epilepsy, among other disorders.

 Despite the growing interest in DBS, Hariz and Hariz

 recently warned against the testing and touting of DBS for “dubious indications,” such as enhancing normal cognition and treating antisocial behavior.

The DBS procedure involves implanting electrodes within specific brain circuits to modulate the circuits’ activity, either to suppress pathological neuronal activity or to drive underactive output, according to Lozano.

“Electrodes are commonly placed with patients fully awake, which allows the surgeon to pinpoint the precise location in the brain using microelectrode recordings of neurons at the target,” he wrote in the editorial. “The surgeon can also gauge the patient’s response to stimulation, which helps guide the final placement of the electrodes. The electrodes are then connected to an implanted pulse generation (along the lines of a standard cardiac pacemaker), which can be programmed to deliver continuous stimulation for several years-batteries last 4 to 5 years or longer with recharging.”

“There have been several failed medication trials for Alzheimer disease recently,” Giacobbe noted. “Our current therapeutics are really only palliative, they don’t address the core issue of plaques and tangles, so there is a great need for some new treatments.”

DBS’s potential for treating Alzheimer disease was discovered “quite unexpectedly” by Lozano’s team while they were using fornix/hypothalamus DBS to treat a patient with morbid obesity. The patient experienced memory improvement.

These findings led Laxton, Lozano, and colleagues at the University of Toronto to develop a phase 1 trial of fornix/hypothalamus DBS in 6 patients with early Alzheimer disease who continued to receive medication treatment.

 The study involved bilateral DBS implantation, detailed neuropsychological and neurological testing, and brain imaging to detect alterations in brain activity induced by stimulation. The patients received continuous stimulation for 12 months.

Increased glucose metabolism was observed in the temporal and parietal cortical areas at 1 month in all patients and was sustained in most of the affected areas at 1-year follow-up. Some patients showed possible improvements or slowing of anticipated cognitive decline at 6 and 12 months based on the cognitive subscale of the Alzheimer Disease Assessment Scale and the Mini-Mental State Examination (MMSE). For example, the rate of decline on the MMSE in the 11 months preceding surgery was 2.8 compared with 0.8 in the 11 months after surgery.

 Lozano’s research team analyzed results for 5 of the 6 patients in the phase 1 trial.

 The 5 had been studied with the same PET scanner. The scans measured regional cerebral glucose metabolism preoperatively, after 1 month, and after 1 year of continuous DBS.

The researchers’ functional connectivity analysis demonstrated increased cerebral metabolism in cortical-subcortical and cortical-hippocampal networks.

“The persistent cortical metabolic increases after 1 year of DBS were associated with better clinical outcomes in this patient sample and were greater in magnitude and more extensive in the effects on cortical circuitry compared with the effects reported for pharmacotherapy over 1 year in Alzheimer disease,” the team concluded.

Currently, a double-blind, randomized, controlled study is under way at 6 sites in North America to evaluate the safety, efficacy, and tolerability of DBS of the fornix in patients with mild, probable Alzheimer disease.

“We are comparing active stim­ulation to sham stimulation,” Giacobbe said. The study, he explained, will help answer the questions of whether it is the active stimulation that is helping patients get better or other factors, such as coming to appointments and related nonspecific effects.

Called ADvance, the proof-of-concept study initially involves 20 people aged 55 to 80 years. It will compare the effects of DBS turned on with those observed with the system turned off. The patients will undergo regular physiological, psychological, and cognitive assessments for a year, at which time those patients in the “off” group will be eligible to have the system activated. The study sponsor is Functional Neuromodulation Ltd, of which Lozano is a company co-founder and chair of its scientific advisory board; Medtronic is providing DBS devices.

“All sites are actively recruiting patients,” said Dan O’Connell, company co-founder and chief executive officer. The 6 sites are Toronto Western Hospital; Johns Hopkins Bayview Medical Center in Baltimore; the Banner Alzheimer’s Institute in Phoenix; the University of Florida Center for Movement Disorders and Neurorestoration at Gainesville; the University of Pennsylvania; and Brown University in Providence, RI.

The 20 patients should be enrolled and implanted with the device by the second quarter of next year, O’Connell said, noting, “If all goes well and DBS is found to be reasonably safe and effective, the study may be expanded to 40 patients.”

Asked about informed consent concerns, Giacobbe said the sites are recruiting patients with early Alzheimer disease only, because of the complexities of consent and because intervening early in the disease’s course will facilitate maximization of patients’ functioning.

DBS has been studied in a small number of clinical trials to treat patients with TRD.

Estimates are that 10% of all depressed patients will become resistant to available treatments, including ECT, so “new options are needed,” Mayberg told 

Based on preliminary observations that the subgenual cingulate region (Brodmann area 25 [BA25]) of the brain is metabolically overactive in TRD, Mayberg and colleagues

 in Toronto studied whether DBS to modulate BA25 could reduce the elevated activity and produce clinical benefit for 6 patients with refractory depression. In a study supported by a NARSAD grant, chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with “a striking and sustained remission of depression in 4 of 6 patients” at the end of 6 months, without changes in concurrent medications.

Following the original study, the Toronto team expanded the sample to 20 patients and reported on 12-month outcomes.

 The response rate was 60% (with response defined as a decrease of 50% or greater in total score on the 17-item Hamilton Depression Rating Scale [HAM-D]) and the remission rate was 30% (with remission defined as a HAM-D score of 7 or less).

In 2011, the researchers reported on the extended follow-up of the patients with data from 3 to 6 years after implantation.

 “The cumulative duration of follow-up was 70 patient years,” Giacobbe said. The percentage of patients who responded was 62.5% after 1 year, 46.2% after 2 years, 75% after 3 years, and 64.3% at the last follow-up visit. More than one-third of patients were in remission at year 3 and at last follow-up.

“We also looked at their quality of life,” said Giacobbe. “Not only their mental health quality of life, but their physical well-being, such as vitality and energy, seemed to improve over time.”

Three of the 20 died-1 of cancer; 1 a likely suicide; and 1 a sudden unexplained death, which was considered a possible suicide.

“We have to be extremely vigilant, because this is a group that has been extremely depressed for a very long time. Even 5 to 6 years later, they still need active psychiatric and neurosurgical follow-up,” Giacobbe said.

At the UHN, he added, psychotherapy is offered after DBS. Patients seem to benefit more from post-DBS psychotherapy than pre-DBS psychotherapy. Many patients, he said, feel their “cognitive cloudiness” is lifting and they are no longer actively depressed, so they want to re-enter psychotherapy to sort out job issues, inter-personal relationships, and other difficulties.

In a pilot study sponsored by St Jude Medical, Lozano, Giacobbe, and several others conducted a prospective open-label trial of subcallosal cingulate DBS for 12 months in patients with TRD.

 The Canadian study involved 21 patients at 3 centers-Vancouver, Montreal, and Toronto. Overall, at 6 months, 48% of the patients responded (50% reduction in the 17-item HAM-D), and at 12 months, 29% responded. Published this year, the study results demonstrated that clinical effects of DBS for TRD are reproducible across centers, Giacobbe said.

Also testing subcallosal cingulate DBS is the BROADEN (BROdmann Area 25 DEep brain Neuromodulation) study to evaluate the safety and effectiveness of DBS in treatment-resistant severe MDD. This 6-month, blinded, sham-controlled clinical trial sponsored by St Jude Medical is under way at some 20 sites in North America.

At Emory University, Mayberg and colleagues are conducting further studies to examine sub-callosal cingulate efficacy and mechanisms in various subgroups, including unipolar and bipolar depressed patients.

 reported their first results of a DBS trial that included a 4-week sham stimulation phase; a 24-week, open-label, active-stimulation phase; and an observational follow-up phase.

Performed under a physician-sponsored investigational device exemption and supported by grants from the Dana Foundation, the Stanley Medical Research Institute, and the Woodruff Foundation, the study involved 17 patients, 10 with MDD and 7 with bipolar II who were experiencing depression.

After 2 years of chronic stimulation involving 12 patients, Holtz­heimer and colleagues found patient response and remission rates were high (92% response, and 58% remission). In addition, patients who achieved remission did not experience a spontaneous relapse, efficacy was similar for MDD and bipolar II patients, and no patient experienced a hypomanic or manic episode during the study.

Beyond BA25, other brain targets are being evaluated in both open-label DBS trials and controlled clinical trials. These areas include the nucleus accumbens, ventral capsule/ventral striatum, lateral habenula, and anterior thalamic peduncle. DBS trials for depression are also being conducted in Europe.

Like any other brain surgery, DBS includes risk of stroke, hemorrhage, seizure, and infection, according to Mayberg and Giacobbe. There are also risks with general anesthesia and with possible equipment malfunction or breakage.

“DBS surgeons quote about a 5% risk of a serious event occurring during the procedure,” Giacobbe said.

Regarding continued trials of DBS for depression, both Giacobbe and Mayberg remain highly committed and optimistic. For Giacobbe, it’s the possibility of advancing treatment options and being “on the cusp of making some meaningful changes.” For Mayberg, it is “seeing that our research can make a difference” and “seeing patients get their lives back.”

 Lozano AM. Deep brain stimulation therapy. 

 Lyons MK. Deep brain stimulation: current and future clinical applications. 

 Hariz MI, Hariz GM. Hyping deep brain stimulation in psychiatry could lead to its demise. 

 Hamani C, McAndrews MP, Cohn M, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. 

 Laxton AW, Tang-Wai DF, McAndrews MP, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer’s disease. 

 Laxton AW, Lozano AM. Deep brain stimulation for the treatment of Alzheimer disease and dementias. 

Smith GS, Laxton AW, Tang-Wai DF, et al. Increased cerebral metabolism after 1 year of deep brain stimulation in Alzheimer disease. 

 Mayberg HS, Lozano AM, Voon V, et al. Deep brain stimulation for treatment-resistant depression. 

, et al. Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. 

 Kennedy SH, Giacobbe P, Rizvi SJ, et al. Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. 

 Lozano AM, Giacobbe P, Hamani C, et al. A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. 

 Holtzheimer PE, Kelley ME, Gross RE, et al. Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. 

The evolution of deep brain stimulation for various neuropsychiatric disorders results from advances in structural and functional brain imaging, increased understanding of neurocircuitry of the brain, and improvements in neurosurgical techniques and equipment.

Psychiatric Times Vol 29 No 12

Takotsubo Cardiomyopathy

Glutamate and Psychiatry in 2012-Up, Up and Away!

New Drug Developments for Bipolar Mania

Deep Brain Stimulation: New Promise in Alzheimer Disease and Depression?

Intimate Portrait: Marsha D. Rosenberg, MD

Penis Size: A Consideration of Fantasy and Reality (With Only a Few Puns)

Networking, Professionalism, and the Internet

Introduction: Navigating the Waters of Digital Technology

Computers in the Consulting Room

New Risks to Confidentiality in the Modern Era