Bipolar Disorder Uncovered

Understanding And Treating Bipolar Disorders

Understanding And Treating Bipolar Disorders

Are You Extremely Happy One Moment and Extremely Sad The Next? Are You On Top Of The World Today And Suddenly Down In The Doldrums Tomorrow? Is Bipolar Disorder Really Making Your Life Miserable? Do You Want To Live Normally Once Again? Finally! Discover Some Highly Effective Tips To Get Rid Of Bipolar Disorder And Stay Happy And Excited Always! Dont Let Bipolar Disorder Ruin Your Life Anymore!

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Married To Mania

This eBook is the key to knowing if you are married to a bipolar spouse, and gives you the keys to what to do about it. Often, being married to a bipolar spouse can be one of the hardest things you go through in your life because emotions in your house can change drastically, and completely without warning. This book gives you the tools to deal with unexpected anger outbursts and guilt that many spouses feel. This book will teach YOU how to deal with feelings of guilt that you may feel towards yourself, even though you have done everything you possibly can to make your marriage work. When you get this eBook, you can order a physical copy of the book and get FREE shipping. Also, you get two bonus eBooks when you order: The Spouse's Guide to Bipolar Disorder Vocabulary, which give you the tools you need to talk to doctors and psychiatrists, and The Bipolar Disorder Rolodex which gives you the latest in bipolar disorder research. It is hard to go through a bipolar marriage without help; now you don't have to.

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Bipolar Disorder in Children

Manic-depression Bipolar disorder (BD) is a chronic psychiatric condition that occurs throughout the life cycle. It is characterized by several different mood states ( bipolar disorder). Pediatric BD (PBD) is oftentimes associated with psychiatric comorbidi-ty. When bipolarity does occur in children and adolescents, it is usually serious, chronic, and debilitating (McClellan et al. 2007). Therefore, treatment research has considered means by which to reduce the symptomatology and suffering associated with BD in the young.

Specific Metabolic Features of Women with Bipolar Disorder

And a propensity towards higher waist circumferences 10 . Obese patients with either BD or schizophrenia are more likely to be women 30 , and weight gain has been shown to be associated with female sex 31 . An evaluation of data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) demonstrated greater rates of obesity in bipolar women (31 ), compared to bipolar men (21 ) in contrast, there were greater rates of overweight in bipolar men (38 ), compared to women (22 ) 32 , a finding consistent with previous studies 33 . Women with BD appear to have a higher likelihood of increased waist circumference than men with BD, suggesting a sex-specific vulnerability to IR in BD. Changes in weight and appetite are found more commonly in women than in men with BD 34, 35 . Higher rates of thyroid and eating disorders are seen in women with BD 36 . Factors that influence the onset and maintenance of obesity in BD include both gender and eating behavior 37 . Similarly,...

Burden And Outcome Of Bipolar Disorder

BPAD are chronic disorders with a high rate of recurrence and relapses. More than 90 of individuals who have a single manic episode will have future episodes (Hopkins and Gelenberg, 1994). Ten to 15 of patients will have more than 10 episodes in their life. Bipolar disorder is therefore one of the leading causes of disability which contributes to the important economic burden of bipolar disorder to society. Patients with BD suffer great losses in productivity, with more bed rest and absenteeism days (see Pini et al., 2005 for review). The economic burden was estimated in a cost-to-illness study around US 45 billion in 1991 in the USA, representing 70 of the annual cost of schizophrenia (Wyatt and Henter, 1995). Worldwide, bipolar disorder is listed as the sixth leading cause of disability (Murray and Lopez, 1996).

Overlap Between Schizophrenia and Bipolar Disorder

It is highly heritable although not entirely so, with environmental factors contributing to onset and modifying its course. These factors are broadly conceptualized as stress, with maternal influenza in the second trimester and secular famine contributing as well. Strikingly, only half of monozygotic twins are concordant for schizophrenia. Multiple genes of small effects are generally believed to be the basis for the genetic vulnerability to schizophrenia, but there is increasing evidence that highly penetrant, single, large deletions or insertions (copy number variations) may be causal. There is much overlap between schizophrenia and bipolar disorder with regard to susceptibility genes, phenomenology, and response to treatment therefore, the ensuing discussion of the 5-HT2C receptor as a target for schizophrenia and its treatment is likely to be highly relevant to bipolar disorder as well. Schizophrenia affects about 1 of the population worldwide, and bipolar disorder affects a...

The Classifications Of Bipolar Disorders

The DSM-IV distinguishes between Bipolar I Disorder (BPAD I), Bipolar II Disorder (BPAD II), Cyclothymic Disorder and Bipolar Disorder Not Otherwise Specified. BPAD I is defined as episodes of mania (with or without major depressive episode) and BPAD II as recurrent episodes of major depression with hypomanic episodes. Cyclothymic Disorder is defined as the presence, for at least 2 years, of numerous periods with hypomanic symptoms and numerous periods of depressive symptoms that do not meet criteria for major depression. The Bipolar Disorder Not Otherwise Specified includes disorders with bipolar features that do not meet criteria for any specific bipolar disorder. In addition to manic, hypomanic and major depressive episodes, the DSM-IV describes mixed episodes where the criteria are met both for a manic episode and for a major depressive episode. The term of dysphoric mania has been proposed since phenomenologic studies have shown that patients with mania experience irritability,...

Series Editors Introduction

The book chapters are logically organized in three major sections. The first section provides the reader with the basics of brain structure and physiology including a review of the triggers for electrical activity within the central nervous system. This section also contains a well organized chapter that outlines the historic beginnings of the KD and its establishment as a treatment for epilepsy. Unique chapters in the second section include individual chapters covering the perspectives of the physician, dietician and nurse in the use of the KD followed by detailed chapters on its efficacy in children as well as in adults. A hallmark of the second section is the detailed assessment of the indications for and the contraindications and or complications that arise from using the KD. Thus, this volume provides the full range of information concerning the treatment of seizures with the KD. Another advantage of this volume is the inclusion of specific chapters on the metabolic changes that...

Serotonin Transporter And Antidepressant Anxiolytic Response

Bipolar disorder, depressed (n 68) Bipolar disorder, depressed (n 22) Bipolar disorder (n 67), controls (n 103) Serretti et al. 2001 Bipolar disorder (n 167), Mundo et al. 2001 Bipolar disorder, antidepressant-induced mania, IM+( n 27), bipolar disorder, IM-( n 29) Rousseva et al. Bipolar disorder 2003 (n 305)

Current Concepts and State of Knowledge Introduction

By convention, the term psychopharmacology is applied to drugs that are used to treat psychiatric disorders. Such drugs are termed psychotropic drugs. Psychopharmacolo-gy is usually grouped with the discipline of neuropharma-cology which is concerned with the application of drugs for the treatment of neurologically based disorders. In reality, these areas often overlap. For example, several antiepileptic drugs are used in the treatment of bipolar disorder. Perhaps a more general term should be used to cover all pharmacologically active substances that directly influence brain function.

Characterization Of Depressive And Anxiety Disorders

Clinical depression must be distinguished from normal grief, sadness, disappointment, and the dysphoria or demoralization often associated with medical illness. The condition is underdiagnosed and frequently undertreated. Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, lack of pleasure, self-deprecation, and variable agitation or hostility. Physical changes also occur, particularly in severe depression, including insomnia or hypersomnia altered eating patterns, with anorexia and weight loss or sometimes overeating decreased energy and libido and disruption of the normal circadian and ultradian rhythms of activity, body temperature, and many endocrine functions. As many as 10-15 of individuals with severe clinical depression, and up to 25 of those with bipolar disorder, display suicidal behavior at some time. Depressed patients usually respond to antidepressant drugs, or, in severe or...

Choice Of Antidepressant Medication And Dosing

The safe and effective treatment of bipolar depression is a difficult clinical challenge. This condition sometimes is misdiagnosed in patients with bipolar disorder who present with mixed dys-phoric-agitated moods, who then are inappropriately treated with an antidepressant without a mood stabilizing agent to protect against worsening agitation or mania. For this reason, the management of manic, mixed, and depressive mood states in bipolar disorder best relies on lithium or other mood-stabilizing agents, notably the anticonvulsant lamotrigine, as the primary treatment (see Chapter 18). An antidepressant can be added cautiously and temporarily to treat bipolar depression, but the additional benefit and safety of sustained combinations of an antidepressant with a mood stabilizer are unproven. The combination SSRI atypical antipsychotic (fluoxetine olanzapine symbyax) is FDA-approved for treatment of depressive episodes associated with bipolar disorder. The natural history of major...

Pharmacological Interventions

Sibutramine affects the reuptake of norepinephrine, serotonin and dopamine, and was originally thought to be a potential antidepressant compound, but was ultimately commercialized as a weight loss agent. Sibutramine was tested in a 12-week doubleblind, randomized, placebo-controlled study in 37 overweight and obese subjects taking olanzapine for schizophrenia or schizoaffective disorder 70 . For the first 8 weeks all subjects participated in weekly group sessions focused on nutrition and behavioral modification. Although the sibutramine group exhibited a mean increase in systolic blood pressure of 2.1 mm Hg, and presented with a higher rate of anticholinergic side effects and sleep disturbances, greater weight loss was observed at week 12 versus placebo (-3.8 vs. -0.8 kg). A similarly designed study with clozapine conducted among 21 patients by the same research group failed to demonstrate a therapeutic advantage for adjunctive sibutramine 71 . Because sibutramine affects serotonin...

Prevalence of Glucose Abnormalities in Schizophrenia

Over the last 5 years, data have begun to emerge on the incidence of DM in schizophrenia cohorts. These data are also complex to interpret as the incidence and prevalence of DM in the general population is rising. The question to focus on is whether the incidence rate of DM is rising faster in subjects with serious mental illness (SMI) than in the general population. This is not a question that can be answered at the present as screening bias in both populations remains both a caveat and a confounder. Some evidence that the incidence rate of DM is rising to a greater extent in the SMI population than in the general population derives from a large USA cohort study of inpatients with schizophrenia and bipolar disorder. In this cohort, the prevalence of diabetes increased from 6.9 in 1997 to 14.5 in 2004 16 with associated increases in incidence rates of diabetes from 0.9 in 1997 to 1.8 in 2004. During the same period,

Potential Pathophysiological Mechanisms for Glucose Elevation

There are a number of studies that suggest a genetic overlap between diabetes and schizophrenia and bipolar disorder 61 . Some preliminary data from a small study in subjects with schizophrenia support a role of the MTHFR genotype in determining a predisposition to insulin resistance 62 .

Management of the Psychotic Patient

Summary This article reviews the pharmacologic management of the psychotic patient, to familiarize oral and maxillofacial surgeons with the care of these patients. The author notes that the trend to outpatient care extends to the psychiatric patient and more health care providers will be faced with the care of this patient population. The author reviews potential drug interactions and clinical considerations for patients already under maintenance therapy. The article covers antipsychotic agents, mood disorders, HCAs (including tricyclic drugs), MAOIs (derivatives of hydrazine or amphetamine), SSRIs (antidepressants), bipolar disorder, and antianxiety agents, specifically benzodiazepines, barbiturates, and buspirone. The emphasis in each section is on pharmacodynamics, drug interactions, and anesthetic concerns. 3 tables. 25 references.

Therapeutic Opportunities In The Early Stages Of Ad Pathology

Resulted in decreased neuronal loss and consequently improved motorfunction, as well as increased lifespan. Another way to employ protein quality control to tackle neurodegeneration is via the UPR. Recently, the compound salubrinal was identified as an inhibitor of eIF2a de-phosphorylation and shown to protect against ER stress-induced cell death 95, 96 . Salubrinal is protective in a Parkinson's disease cell model 97 , indicating its potential for the treatment of neurodegenerative diseases. A drawback is that constitutive phosphorylation of eIF2a is unlikely to present a long-term treatment opportunity 98 , therefore more selective targeting should be investigated. Valproate, a drug widely prescribed in the treatment of bipolar disorder and epilepsy, has been shown to increase the levels of BiP GRP78 and other ER chaperones 99, 100 . Although valproate increases ER chaperones it has been reported that ER stress induced cellular dysfunction is reduced by valproate through inhibition...

Postmortem Studies of 5HT2C Function

Decreased messenger ribonucleic acid (mRNA) expression of 5-HT2C receptors has been reported in postmortem prefrontal cortex tissues in 55 patients with schizophrenia and 55 controls (Castensson et al. 2003). Castensson et al. (2005) reported that the decrease in expression of the 5-HT2C receptor was not related to drug action and might be a core feature of the illness. Decreased expression of the 5-HT2C receptor has also been reported in bipolar disorder patients (Iwamoto and Kato 2003). Diminished 5-HT2C receptor expression would be expected to facilitate limbic DA release.

PET Tracers of Cerebral Metabolism and Blood Flow

PET has been used to assess functional activity of brain regions, both in the resting state and in response to various stimuli. The methods used include use of FDG-PET and radioactive 15O H2O-PET to study metabolic activity and blood flow, respectively. Figure 10-2A shows a picture of increased cerebral blood flow to paralimbic regions during a sad mood induction task (to be described later) using H2O-PET. In contrast, Figure 10-2B shows metabolic activity differences among depressed versus healthy patients using FDG-PET. These modalities have been effectively used to study a variety of mental phenomena and have been of considerable benefit in enhancing our understanding of psychiatric disorders. Of particular interest have been studies using PET to understand the biological basis of schizophrenia (Fujimoto et al. 2007 Lange et al. 2005), bipolar disorder (Post et al. 2003), depression (Mayberg 2003b Neumeister et al. 2004), substance abuse and craving (Kilts et al. 2004), PTSD...

Magnetic Resonance Spectroscopy

MRS technology is based on the fact that MR acquisition involves receiving echoed RF waves of multiple cellular chemical constituents. The individual chemical and metabolite constituents could be measured by suppressing the resonance frequency of water molecules. A detailed exposition of the various types of MRS techniques is beyond the scope of this chapter, and the reader is referred to excellent reviews on the topic (Mason and Krystal 2006 C. M. Moore et al. 1999). Among the markers currently being researched are M-acetylaspartate (NAA), glutamate glutamine (glx), myoinositol (ml), choline (Cho), glutathione, creatine, GABA, phosphomonoester (PME), and phosphodiester (PDE) (Lyoo and Renshaw 2002). An example of an MRS spectrum from a healthy control subject is provided in Figure 10-6. Using this approach, Frye et al. (2007)were able not only to demonstrate elevated glutamate glutamine (glx) in anterior cingulate medial prefrontal areas of patients with bipolar depression but also...

Tolerability and Safety

In general, mood-stabilizing medicines have to be reasonably well tolerated because patients are expected to take them week in and week out for many years - often indefinitely. There is a tendency for doctors to underestimate the adverse impact of medicines on their patients. The most important adverse subjective effects of psycho-tropic drugs that are used to treat bipolar disorder tend to be tiredness, sedation, and weight gain. In addition, lithium can produce tremor, increased urine volumes, and thyroid dysfunction. Attention to minimizing these problems (by optimizing doses) is essential for good adherence to prescribed medicines. Weight gain was formerly seen as a largely cosmetic problem. It is now realized to be a much more important because obesity combined with lack of exercise and smoking is associated with the so-called metabolic syndrome. This is a composite term for biochemical, blood pressure, and weight indices associated with older age and higher body mass index. It...

Oxcarbazepine Definition

Oxcarbazepine is used primarily as an antiepileptic drug to control seizures in patients. However, it has gained utility in various mood disorders including anxiety, depression, bipolar disorder, as well as in the management of neuropathic pain and migraine. Oxcarbazepine is structurally similar to an older antiepileptic carbamazepine, and like carbamazepine works by reducing excessive or inappropriate excitability of nerve cells that normally occurs in conditions such as epilepsy and neuropathic pain. Bipolar Disorder

Role of Pharmacotherapy

Axis I and Axis II disorders often co-occur with PG (Ibanez et al. 2001) therefore, it is clinically relevant to consider treatment approaches based on types of co-occurring disorders (e.g., alcohol or drug use disorders, bipolar disorders, anxiety disorders, or major depression). Given the proposed mechanisms of action of specific psychotherapies and pharmacotherapies, it is also important to consider specific neurobiological aspects of PG (e.g., opioid system, serotonin system) when considering treatments. This chapter will focus on findings from placebo-controlled studies and cite references that review these and other studies. For additional information about specific studies, readers are encouraged to see the original sources cited in the review articles. Bipolar disorder and PG share characteristics including impulsive behavior, risk taking, fluctuations in mood, and poor judgment (Iancu et al. 2008). Additionally, PG often co-occurs with bipolar disorders. Should the...

Perphenazine Definition

Perphenazine is a first-generation antipsychotic medication that acts as a dopamine D2 receptor antagonist. It is a piperazine-phenothiazine derivative, also available as depot medication. Perphenazine is indicated for the treatment of schizophrenia and other psychoses, mania in bipolar disorder, and the short-term adjunctive treatment of severe anxiety, psychomotor agitation, excited or violent states. It can also be used as an anti-emetic drug. Extrapyramidal motor symptoms occur, especially dysto-nia especially at high doses.

Quetiapine Definition

Receptors, with a generally broad receptor-binding profile. Quetiapine is indicated for the acute and maintenance treatment of schizophrenia and bipolar disorder. Because of its low propensity to cause extrapyramidal symptoms, the drug can be used to treat psychosis in Parkinson's disease. It is a dibenzothiazepine derivative that dissociates quickly from the D2 receptor. Fast-dissociating D2 antagonists have been hypothesized to allow dopamine to still interact with the D2 receptor under conditions of phasic bursts of dopamine release, thereby eliciting its normal effects in the nigrostriatal and tuberoinfundibular pathways and reducing the risk of side effects. Possibly because of these properties, the risk of extrapyramidal symptoms and effects on prolactin release is lower than for first-generation antipsychotics. Quetiapine has relatively prominent histamine H1 antagonistic effects that are likely to contribute to its sedative properties. The drug also has an active metabolite,...

In Vivo Efficacy of ARA014418

The efficacy of AR-A014418 has been studied in different in vivo models of tauopathy. AR-A014418 has demonstrated a reduction in both the phosphorylation of soluble tau and the formation of insoluble tau (PHF tau), and a reversal of microtubule dysfunction in human tau tg mice and JNPL3 mice (expressing tau mis-sense mutation P301L) 75 . Overexpression of the wt human Tau 0N3R isoform in Drosophila motor neurons leads to disrupted ax-onal transport resulting in vesicle aggregation and loss of locomotor function accompanied by neuronal cell death. Co-expression of constitutively active GSK-3 and Tau 0N3R in Drosophila motor neurons further enhances axon transport and locomotor phenotypes 73 . Administration of AR-A014418 in Drosophila reverses both the axonal transport and locomotor deficits, suggesting that this phenotype is GSK-3 dependent. AR-A014418 induces reduced immobility time in forced swim tests and inhibited amphetamine-induced activity in rats 90 . These behavioural changes...

Proteinassociated Cns Diseases

Bipolar Disorder Bipolar (manic-depressive) disorder is characterized by cycling episodes of depression and mania with a lifetime prevalence of 1.2 (Weissman 1988). The postmortem frontal cortex tissue of bipolar victims shows enhanced receptor-to-G protein coupling along with increased trimeric states of the G proteins (Friedman 1996). This study shows an increased expression of Gas proteins without changes in levels of other G proteins, but all G proteins show a higher propensity to be in their trimeric state. The higher fraction of trimeric G proteins may indicate a supersensitization of G protein-mediated signaling in patients with bipolar disorder. Lithium is a common antimanic agent. In agreement with the possibility that bipolar disorder may be partially due to an increase in Gas protein levels, bipolar patients treated with lithium showed a decrease in Gas protein levels in the occipital cortex (Dowlatshahi 1999). Lithium treatment also decreases ADP-ribosylation of Gai...

Disorders Of Overt Emotional Behaviour

Moria is the term applied to mood elevation (excitement or euphoria), often of a very caustic nature, occurring as a result of (and in spite of) brain disease or injury that results in significant disability or injury. It occurs in the absence of a premorbid history of hypomania or bipolar disorder. It must not result from pharmacological treatment or illicit drug use. Moria is commonly the result of right-hemispheric,3 especially orbitofrontal parenchymal, lesions.23 However, it has been reported after lesion-ing of the ventromedial caudate nucleus14 as well as long-standing right frontoparietal hypoperfusion.23 It is often accompanied by Witzelsucht (crass facetiousness and the repetitive telling of inappropriate, often sexual jokes).23

Interactions With Other Drugs

DRUG TREATMENT OF BIPOLAR DISORDER Treatment with Li+ ideally is conducted in cooperative patients with normal Na+ intake and with normal cardiac and renal function. Occasionally, patients with severe systemic illnesses are treated with Li+, provided that the indications are compelling. Treatment of acute mania and the prevention of recurrences of bipolar illness in otherwise healthy adults or adolescents currently are the only uses approved by the FDA, even though the primary indication for Li+ treatment is for long-term prevention of recurrences of major affective illness, particularly both mania and depression in bipolar I or II disorders. Li+ sometimes is used as an alternative or adjunct to antidepressants in severe, especially melancholic, recurrent depression, as a supplement to antidepressant treatment in acute major depression, including in patients who present clinically with only mild mood elevations or hypomania (bipolar II disorder), or as an adjunct when later response...

Hypothalamic Pituitary Adrenal HPA Axis in Depression CRF

Neurotransmitters Concentration

A primary focus on the HPA axis and, more recently, LCSPT tract risks subsuming findings of alterations in other measures as merely secondary. As will be succinctly reviewed in what follows, investigators have reported that other neuroendocrine or neurotransmitter systems are just as consistently dysregulated in depression as the primary HPA one. As cataloged in Table 1 and conceptualized in Figs. 1 and 2, these constitute a multitude of complex and potentially inter-related findings relevant to the pathophysiology and treatment of unipolar depression(s). As noted at the outset, trying to fit manic-depressive illness and unipolar depression into a common pathophysiologic model is an even more difficult task, particularly when one considers the differences in spectrum of efficacy between putative mood stabilizers and antidepressants. We will, therefore, continue to restrict our focus and only occasionally refer to those studies on bipolar disorder that help to elucidate investigations...

Biogenic Amines in Neurodegenerative and Neuropsychiatric Diseases

Neuropsychiatric disorders involve abnormalities in cerebral cortex and limbic system (thalamus, hypothalamus, hippocampus, and amygdale) 48 . Behavioral abnormalities are the hallmarks of many neuropsychiatric diseases, including schizophrenia, depression, and compulsive and bipolar disorders. Neuochemical studies indicate that in neuropsychiatric diseases several biogenic amine neurotransmitter systems (dopamine, serotonin and epinephrine) are simultaneously altered within a single microcircuit and each transmitter system shows circuitry changes in more than one region. Changes in microcircuits and neurotransmitters (synthesis and transport) may not only vary on a region-by-region basis, but also from one neuropsychiatric disease to another. Both macro- and microcircuitry within the specific brain system (such as limbic system) may serve as 'triggers' for the onset of neuropsychiatric condition 49,50 . It is also reported that alterations in cerebral blood flow and glucose...

Neuroimaging Synonyms

Neuroimaging is a family of techniques used for obtaining images of the structure or the function of the human brain. Neuroimaging studies investigate structural and functional brain maturation in health or in diseases of the brain, such as schizophrenia, bipolar disorder, depression, ADHD, drug dependence, and autism. These studies often aim to find genetic and environmental markers of variance in brain structure and function over time. Through additions to diagnostic radiology, neuroimaging has broadened to become a distinct field in neuroscience. The neuroimaging techniques that are currently used in research include single-photon emission computerized tomography (SPECT), positron emission tomography (PET), distinct forms of magnetic resonance imaging (MRI) including structural and functional MRI, MR spectroscopy (MRS), and diffusion tensor imaging (DTI).

Trace Amine Associated Receptors

Human TAAR6 expression has been detected in the amygdala, hippocampus and kidney 3 . Particular interest has been paid to human TAAR6 as the SCZD5 schizophrenia susceptibility locus 44 was reported to correlate specifically with polymorphisms of TAAR6 54 . Confirmatory linkages between TAAR6 and schizophrenia and possibly bipolar disorder have subsequently been reported 55-59 , although others have reported marginal or no linkage 60-66 . The lack of a consistent replication of TAAR6 linkage to schizophrenia may be a function of one or more factors including disease heterogeneity, ethnic variation of populations studied and the apparent high mutation (rapidly evolving) rate of TAAR 66 .

Physiological Manipulations

Direct administration of naturally occurring neuropeptides, hormones, and cytokines has been used in animal models to identify physiological factors that induce behavioral symptoms of depression in humans. For example, chronic stress levels of cortisol systemically administered to squirrel monkeys impair prefrontal-dependent cognitive control of impulsive behavior (Lyons et al. 2000). Cortisol administered to healthy humans induces prefrontal-dependent cognitive impairments that resemble those that are caused in humans by prefrontal lesions (Lupien et al. 1999 A. H. Young et al. 1999). Humans with psychotic major depression consistently present with endogenous hypercortisolism (Nelson and Davis 1997), and patients with psychotic major depression are impaired on standardized tests of prefrontal cognitive functions (Schatzberg et al. 2000). Based on these findings, drugs that block cortisol at the receptor level are now being tested as novel treatments for psychotic major depression...

Selection of ACD versus Antidepressant Pharmacotherapy

Selection of medication options for patients needs to be individualized, taking into consideration the tolerability of side effects and safety of use of particular medications in the context of the patient's comorbid medical and psychiatric conditions (Leo 2006). For example, the patient with comorbid depression and or anxiety might be best managed with selection of an antidepressant. On the other hand, ACDs have mood-stabilizing effects that benefit patients with bipolar disorder, schizoaffective disorder, and impulsivity arising from dementia (Chandramouli 2002, Leo and Narendran 1999) therefore, ACD selection for patients with these conditions would be ideal. Regarding medical comorbidities, there are several factors to consider. Heart block, arrhythmias, or severe cardiac disease prohibit use of TCAs. For patients with renal dysfunction, doses of duloxetine, venlafaxine, carba-mazepine, gabapentin, pregabalin, and topiramate would need to be reduced, and if the renal dysfunction...

Genetics Of Anxiety And Related Disorders 21 Anxietyrelated traits in mood disorders

A large body of evidence from family, twin, and adoptee studies has been accumulated that a complex genetic component is involved in anxiety-related traits and in the liability to anxiety spectrum disorders. While genetic research has typically focused either on normal personality characteristics or on psychiatric disorders, with few investigations evaluating the genetic and environmental relationship between the two, it is of critical importance to answer the questions whether a certain quantitative trait etiopathogenetically influences the disorder or whether the trait is a syndromal dimension of the disorder. Nevertheless, some studies have implicated anxiety-related personality traits, such as neuroticism or negative emotionality, in the comorbidity of mood disorders (Kendler et al. 1993a Livesley et al. 1998). Separation of anxiety spectrum disorders from mood disorders including depression and bipolar disorder in current consensual diagnostic systems remarkably enhanced interest...

Serotonin 1a Receptor And Antidepressant Anxiolytic Response

Preliminary evidence that allelic variation of 5HT1A receptor expression influences the response to antidepressant treatment has recently been provided by two independent studies. Serretti and colleagues (2004) assessed the severity of depressive symptoms in 151 patients with major depression and 111 bipolar patients before and following six weeks of treatment with the SSRI fluvoxamine and demonstrate that in bipolar disorder but not in unipolar depression, patients homozygous for the C variant of the HTR1A-1019 polymorphism showed a better response as compared to carriers of the G allele. Interestingly, the results failed to reveal an interaction between the HTR1A-1019 polymorphism and reported effects of the 5HTTLPR. Lemonde et al. (2004) reported that antidepressant response to the SSRI fluoxetine, noradrenaline reuptake inhibitor nefadozone, and 5HT1A agonist flibanserin, which desensitize the 5HT1A autoreceptor as one their mechanisms of action, was associated HTR1A-1019...

Hypothalamic PituitaryAdrenal Axis Dysfunction in Schizophrenia

Lack of or poorly functioning GR can also lead to an overactive HPA axis and such changes have been seen in subjects with schizophrenia. i.e. GR mRNA numbers in the frontal cortices, amygdala and hippocampus (dentate gyrus, CA1, CA3 and CA4) 30, 31 although these changes also occur in other psychiatric illnesses such as bipolar disorder and major depression 32 . Further evidence of GR dysfunction may come from the observation that acutely administered

Human Genetic Variation

Abnormalities, such as translocations, deletions, or duplications of large regions of chromosomes. In a large Scottish pedigree, a balanced translocation between chromosomes 1 and 11 appears causally linked to a series of major psychiatric disorders, including schizophrenia, bipolar disorder, recurrent major depression, and conduct disorder (St. Clair et al. 1990). This balanced translocation (which exchanged parts of chromosome 1 with parts of chromosome 11 to produce two abnormal chromosomes, but no net loss of chromosomal material) disrupts two genes at the translocation breakpoint on chromosome 1, termed disrupted in schizophrenia (DISC) 1 and 2 (Millar et al. 2000, 2001). Subsequent molecular analysis has provided strong evidence that variation in DISC1 can alter the risk for schizophrenia the locus is presently considered by most a confirmed schizophrenia locus (Porteous et al. 2006).

Transport Systems of Biogenic Amines

VAChT gene (VAChT) is expressed in all known major cholinergic neurons in the PNS and CNS. Both VAChT and choline acetyltransferase are encoded by a single genetic locus, suggesting both genes are coregualted. VAChT is a specific marker for cholinergic neurons for studying cholinergic transmission in AD and other nervous system disorders 17-19 . Vesicular monoamine transporter1 gene (VMAT1), also known as SLC18A1, maps to bipolar disorder and Schizophrenia susceptibility locus, therefore, gene has been postulated to play a role in the etiology of these neuropsychiatric disorders 20-22 . The vesicular monoamine transporter 2 gene (VMAT2), also known as SLC18A2, controls loading of biogenic amines including catecholamines and indolamines into synaptic vesicles for exocytotic release 23 . Catecholamines when not transported to synaptic vesicles can be auto-oxidized in the cytosol and produce oxidative stress to the cell. For example, in dopaminergic neurons, VMAT2 is also a target for...

Physiology and disease relevance

The dopaminergic system has been the focus of much research over the past 40 years because several pathological conditions such as Parkinson's disease, schizophrenia, bipolar disorder, manic depression, Tourette's syndrome, and hyperprolactinaemia are believed to be associated with either dopaminergic system dysfunction or side effect profiles of drugs used to treat these disorders. Extensive work has also been performed to analyse the genetic relationship between dopamine receptors and the diseases mentioned above (reviewed in Missale et al. 1998). However, the results that have been produced are equivocal. Thus no linkage of D2 and D4 receptors to bipolar disorder has been found (Missale et al. 1998) and the association between the dopamine D2 receptor gene and susceptibility to alcoholism is controversial (Missale et al. 1998). More recently, some evidence has been reported for the genetic association of dopamine D4 receptor polymorphisms with behavioural disorders such as...

Support for the Serotonin 2C Receptor

In a recent paper, Serretti et al. (2009) also investigated possible associations between personality traits and a panel of markers in both HTR1A and HTR2C receptors in a German sample of suicide attempters and controls and in an Italian sample of mood disorder patients. Analyzing HTR2C haplotypes in the suicide attempter sample, they have found a trend towards significance for reward dependence (RD) score. This link was a replication of the study performed by Ebstein et al. (1997). These findings make it possible to hypothesize a link between personality and HTR2C SNPs, since the presence of similar findings are present in the literature. A recent study by De Luca et al. (2008) analyzed HTR2C variants (Cys23Ser and a common STR in the promoter) in suicide attempters. Their sample was composed of 306 families with at least one member affected by bipolar disorder, and they have studied HTR2C haplotypes with respect to attempter status and the severity of suicidal behavior. The goals of...

Pharmacogenetics In Clinical Research And Drug Development

The need for more disease understanding and greater clarity and understanding of optimal patient drug treatment options is recognized by the NIMH and currently incorporated as part of the NIMH Treatment Research Initiative. This program includes 3 large real-life clinical trials studying the effectiveness of drugs for unipolar depression (STAR*D Sequence Treatment Alternatives to Relieve Depression http stard), schizophrenia (CATIE Clinical Antipsychotic Trials of Intervention effectiveness and bipolar disorder (STEP-BD Systematic Treatment Enhancement Program for Bipolar Disorder (Rush et al. 2003 CATIE, 2003). These clinical studies aim to determine the most appropriate treatment strategies for patients with mood and psychotic disorders. The findings from these studies have the potential to have a major impact on prescribing recommendations for their respective indication. The first data from the STAR*D program is expected in...

Ll Introduction

Lithium, from the Greek word 'lithos' or stone, is the smallest and lightest solid element - a monovalent cation appearing third on the periodic table. It is well known for its use in batteries, metal alloys, glass manufacture and for its clinical use in the treatment of manic depression or bipolar disorder (BD), a chronic disorder which affects between 1 and 2 of the population and is characterized by episodic periods of elevated and or depressed mood.1 This disorder severely reduces patients' quality of life and dramatically increases the likelihood of these patients committing suicide.2 Lithium's clinical role has given rise to extensive amounts of scientific research however, despite this, there is still considerable debate regarding its medicinal targets. It is also unclear how such a structurally simple ion can have such a profound effect on specific and complex medical disorders such as BD.


There are other examples where people have sought more relevant outcomes. For instance, a series of different outcomes related to wart clearance and return emerged from a systematic review of genital wart therapy 27 , while a longitudinal survey of patients with bipolar disorder suggested that success be judged over longer periods because of the sustained nature of the disorder 28 .


Women with bipolar disorder (BD) may have unique risk factors for insulin resistance (IR). Specific periods in a woman's reproductive timeline, specifically pregnancy and after the menopause, may represent times of increased IR. Moreover, women with BD demonstrate higher rates of obesity compared to men with BD, suggesting a sex-specific vulnerability to metabolic sequelae in BD. Additional contributors to metabolic sequelae, such as psychotropic medication, dysregulation of the hypotha-lamic-pituitary-adrenal axis, and genetic influences common in BD, may also manifest differently between the sexes. Several studies have suggested that women with BD may have more menstrual cycle irregularities than women in the general population. It has been hypothesized that such irregularities may be due to endocrinological disorders, such as polycystic ovarian syndrome or to hypo-thalamic-pituitary-adrenal axis dysfunction, both of which are also be associated with IR. Women treated with valproate...


It is clear that transgenic mice modeling different aspects of 5-HT2CR function have provided important and otherwise unobtainable knowledge of how serotonergic neurotransmission affects cellular function and whole organism behavior. In fact, there is still much future work to be accomplished. For example, the generation of currently unavailable mouse models with tailored 5-HT2CR function (e.g., overexpression, lesions, or specific edited receptor isoforms) restricted to important CNS regions, including but not limited to the striatum, nucleus accumbens, bed nucleus of stria terminalis, and amygdala, will further clarify how 5-HT2CRs regulate the behavioral response to environmental stressors and appetitive aversive stimuli. Temporal control of 5-HT2CR function would similarly allow investigators to determine if later-life loss of 5-HT2CR function is ameliorated in the presence of intact function in neonate and young mice, and conversely, if reestablishment of 5-HT2CR function in...


Do these definitions fit for genetic studies In other words, are mood disorders subtypes genetically distinct And are genes that cause a specific disorder completely different from those involved in other disorders, or do they overlap each other Even thought it is possible a clear diagnosis between typical schizophrenia and Bipolar Disorder (BP), genetic distinction between other disorders is not so clear (Winokur 1993 and 1995 Tsuang 1990 Maziade 1995).

GABA Transporter

The neurotransmitter GABA transmits inhibitory signals that reduce excitation and anxiety. A search for selective inhibitors of GABA transporters has led to potent and selective inhibitors of GAT-1 (SwissProt accession number P30531), which is a 12 TMH transporter with homology to LeuTAa 59 . The only clinically approved GAT-1 inhibitor at present is tiagabine 140,141 . Tiagabine is a potent and broad spectrum anticonvulsant drug which does not induce tolerance to the anticonvulsant effect 142 . Tiagabine has also shown promise in clinical trials to treat chronic daily headaches with symptoms of migraine 143 , and it has been suggested from preclinical studies and human studies that tiagabine also possesses anxiolytic properties 141 . Tiagabine has also been reported to be effective in prophylactic treatment of bipolar disorder 144,145 , but its therapeutic potential in this condition has not been established.

Animals and Humans

The preclinical research that contributes to the selection of an IND candidate typically occurs in a relatively well-defined and controlled environment, with the tissue samples and subjects (animals) being studied being relatively uniform in their characteristics. Accordingly, the preclinical research process is relatively straightforward and economical, resulting in data that are generally highly reproducible. This contrasts markedly to the clinical situation where subjects are drawn from a diverse population and where there are many other variables not encountered in the laboratory setting, including differences in diagnostic criteria and stage of the disease. For instance, while schizophrenia can be viewed as a single disorder, there is in fact a major overlap in the symptoms of this condition with bipolar disorder (Marino, Knutsen, & Williams, 2008). Indeed, it has been suggested that schizophrenia may consist of 10 or more discrete disorders

Therapeutic Uses

When combined with other antiseizure drugs, gabapentin is effective for partial seizures, with or without secondary generalization. Gabapentin (900 or 1800 mg day) monotherapy is equivalent to carbamazepine (600 mg day) for newly diagnosed partial or generalized epilepsy. Gabapentin also is used off-label for the treatment of migraine, chronic pain, and bipolar disorder. Gabapentin usually is effective at 900 1800 mg daily in three divided doses, although 3600 mg may be required in some patients. Therapy usually is begun with a low dose (300 mg once on the first day), which is increased in daily increments of 300 mg until an effective dose is reached.

Mood Disorder

There is a general perception that glucose abnormalities in bipolar disorder are not dissimilar to schizophrenia. The recent NICE guidelines for bipolar disorder emphasise the importance of glucose monitoring 30 . The problem is untangling bipolar disorders (all types) from treatment disorders and unipolar depression. Accordingly, definitive data on glucose metabolism is less defined with a complete absence of treatment-naive data. Bipolar Disorder and Glucose There has been awareness for many years that some connection exists between depression and diabetes. The increased usage of antipsychotics in treating major depression may complicate the analysis of the relationship between the disease and the onset of diabetes. A recent large USA chart review found that in a cohort of psychiatric inpa-tients receiving antipsychotics, the largest diagnostic group was major depressive disorder (27.6 of the sample) comparing with schizophrenia (13.8 ) with 54.2 of these depressed subjects...

The Condition

The prevalence of CVD is increased in people with SMI. In a recent retrospective cohort study of 46,136 people with SMI, the rates of CVD in those under 50 years old were 3.6-fold higher in those with schizophrenia and 2.1-fold higher in people with bipolar disorder 2 . The risk of stroke was 2.9- and 3.3-fold higher in people with schizophrenia and bipolar illness respectively. Both sexes were equally affected and traditional risk factors such as smoking and social deprivation did not fully explain this increase. Although the use of antipsychotic medication was associated with coronary heart disease, the risk was greater in those who never used antipsychotics.


In the elderly, it is common for the required dosage to be substantially less than those used in younger people. Side effects are an important guide, as ever, to what the dosage should be. The highest well-tolerated dose (whatever the actual figure) is usually the best choice in bipolar disorder.


A recent study of MetS in patients with bipolar disorder found statistically significant associations only for olanzapine clozapine (p 0.001) and carbamazepine (negatively associated, p 0.018) 34 , suggesting that the 'mood stabilizers' (lithium, valproate, carbamazepine, lamotrigine, gabapentin) do not increase risk. However, many patients in this study who did not have MetS did meet the ATP III WC criterion. In addition, in the present study anticonvulsants as a class were associated with increased risk on the triglyceride and HDL measures, and weight gain is a well-known side effect of both lithium and valproate. Livingstone and Rampes

Lithium Chloride

Lithium has been used to treat bipolar disorders based on its mood stabilising effects for several decades. Considerable effort has been put into understanding the mechanism by which lithium operates. The recent discovery that lithium inhibits GSK-3 at therapeutic concentrations has introduced the possibility that GSK-3 represents a key target of lithium's action in the brain.

Ndi And The V2r

Congenital NDI is a hereditary disease associated with renal tubular resistance to the antidiuretic hormone vasopressin 26 . NDI is most common in its acquired form, due to electrolyte disturbances, urinary tract obstruction, or as a side effect of lithium salts used to treat bipolar disorder 27 . In its congenital form, two primary molecular defects can cause NDI Mutations in the gene encoding the aquaporin-2 water channel (AQP2) lead to the autosomal dominant and recessive forms of NDI 28-30 mutations in the gene (AVPR2) encoding the V2R lead to the X-linked recessive form of NDI and account for

Bipolar Depression

Patients with bipolar disorder present significant clinical challenges, not the least of which are episodes of bipolar depression nearly 50 of such patients are unresponsive to the antidepressant effects of lithium alone (Sachs 1996). This is a particularly difficult clinical problem because antidepressants may precipitate manic episodes in patients with bipolar disorder. Two paroxetine studies have demonstrated the efficacy and safety of this SRI in treating patients with this often treatment-refractory disorder. In one study with lithium-treated patients, Bauer et al. (1999) found paroxetine (20-40 mg day) to be superior to amitriptyline (75-150 mg day), on the basis of the Ham-D and CGI-Severity of Illness (CGI-S) scores, although relatively low doses of amitriptyline were used in the 6-week study. In a multicenter double-blind, placebo-controlled comparison trial, Nemeroff et al. (2001) found no difference in response rates among paroxetine (20-50 mg day), imipramine (150-300 mg...


Theories attempting to explain the possible association between antidepressants and the onset of suicidality have been a part of psychiatric folklore since these medicines became available decades ago. Paroxetine in particular has several characteristics that may explain its implication in suicidal adverse events in children and adolescents with major depressive disorder. As previously noted, it has nonlinear kinetics, such that small dosage increases produce dramatic increases in child serum levels. Such high levels could lead to activation, akathisia, or disinhibition, any of which might explain suicidal thoughts or acts (Brent 2004). This effect is even more dramatic in those children who are slow metabolizers of the CYP2D6 isoenzyme (roughly 10 of the Caucasian population) (Riddle 2004). Additionally, paroxetine has a relatively short half-life (11 hours vs. 5 days with fluoxetine), and limited dosing adherence, not uncommon in children and teens, could lead to SRI discontinuation...


The importance of G proteins and their associated signaling cascades in the etiology of neuropsychiatric disorders is receiving increasingly extensive attention. G proteins and their associated signaling proteins provide intracellular regulation and modulation of extracellular signals, which can be utilized to develop novel pharmacological agents to treat psychiatric disorders. Such medications may not have the specificity of drugs that affect specific receptors. However, medications that address post-receptor signaling proteins may be useful in disorders involving multiple receptor systems, particularly those that utilize common second messenger systems (for example, the treatment of bipolar disorder).

Tamya Kolachana

Badner JA, Gershon ES Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 7 405-411, 2002 PubMed Bailey A, Le Couteur A, Gottesman I, et al Autism as a strongly genetic disorder evidence from a British twin study. Psychol Med 25 63-77, 1995 PubMed Barrett JC, Cardon LR Evaluating coverage of genome-wide association studies. Nat Genet 38 659-662, 2006 PubMed Barrett TB, Hauger RL, Kennedy JL, et al Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder. Mol Psychiatry 8 546-557, 2003 PubMed 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. Mol Psychiatry 13 197-207, 2008a Baum AE, Hamshere M, Green E, et al Meta-analysis of two genome-wide association studies of bipolar disorder reveals important points of agreement. Mol Psychiatry 13...

Treatment Strategies

There exist three primary treatment strategies for disorders of emotional behaviour pharmacological treatment, neuropsychological rehabilitation and ecological manipulation. Alas, few disorders of emotional behaviour have proven amenable to drug treatment. Three major exceptions are abulia, moria and pathological laughing and crying. Abulia may be responsive to low doses of stimulants such as methylphenidate,64 as well as dopamine agonists such as bromocriptine and lisuride.10,65 Moria may respond to standard pharmacological treatments for bipolar disorder. Pathological laughing and crying are often responsive to antidepressants of the selective serotonin reuptake inhibitor class, especially paroxetine and citalopram.66,67


Protein-coupled NPY receptor subtypes, termed Y1-Y5, have been identified and cloned (Redrobe et al. 2002). The NPY receptors Y1 and Y2 are the most abundant and are found in the cerebral cortex, thalamus, brain stem, and hypothalamus (Redrobe et al. 2002). In addition to its role in regulating eating behavior, NPY has been implicated in affective disorders. For example, in a rodent model of depression, chronic antidepressant treatment increased NPY and Y1 mRNA levels (Caberlotto et al. 1998). In humans, cerebrospinal fluid and plasma levels of NPY are lower in depressed patients than in controls (Nilsson et al. 1996 Westrin et al. 1999), and these levels increase after electroconvulsive therapy (Mathe et al. 1996). In addition, NPY mRNA is reduced in the prefrontal cortex of subjects with bipolar disorder (Caberlotto and Hurd 2001) and subjects with schizophrenia (Hashimoto et al. 2008).