Current Psychiatry Reviews

ISSN: 1573-4 005

Current Psychiatry Reviews
Volume 1, Number 3, November 2005

Contents

The Concept of Dysregulated Signal Transduction and Gene Expression in the Pathophysiology of Mood Disorders Pp.227-254
Yogesh Dwivedi
[Abstract]


Is a “Mitochondrial Psychiatry” in the Future? A Review Pp.255-271
Ann Gardner and Richard G. Boles
[Abstract]


Recent Developments in Deception Research Pp.273-279
Catherine J. Hughes, Tom F.D. Farrow, Marie-Claire Hopwood, Angela Pratt, Michael D. Hunter and Sean A. Spence
[Abstract]


Update on the Treatment of Pediatric Obsessive-Compulsive Disorder Pp.281-291
Michael J. Larson, Eric A. Storch, Adam B. Lewin, Gary R. Geffken, Tanya K. Murphy and Wayne K. Goodman
[Abstract]


Antipsychotics in Obsessive-Compulsive Disorder Pp.293-301
Giuseppe Maina, Umberto Albert, Enrico Pessina, Virginio Salvi and Filippo Bogetto
[Abstract]


Towards an Integrated Clinical Psychobiology of Alcoholism Pp.303-312
Colin R. Martin and Adrian B. Bonner
[Abstract]


Transcription and Neurotrophic Factors in Affective Disorders: New Trends in Understanding the Action of Antidepressant Drugs Pp.313-317
Francois P. Monnet
[Abstract]


Clinical Characteristics as Predictors of Response to Fluvoxamine, Paroxetine and Milnacipran in Patients with Depression Pp.319-324
Shigeru Morishita and Seizabur Arita
[Abstract]


Bipolar Depression: The Neglected Realm of Postpartum Disorders Pp.325-329
Verinder Sharma
[Abstract]


The Neurobiology of Love Pp.331-335
Donatella Marazziti
[Abstract]


Involvement of the Serotonergic System in Cognitive and Behavioral Symptoms of Alzheimer's Disease Pp.337-343
María Javier Ramírez, Bárbara Aisa, Francisco Javier Gil-Bea and Beatriz Marcos
[Abstract]


Neurotransmitter Dysfunction and Neurotransmitter Replacement Therapy as Part of Frontotemporal Dementia Treatment Pp.345-351
Martine Vercelletto, Michel Bourin, Lucette Lacomblez, Patrice Verpillat and Pascal Derkinderen
[Abstract]




Abstracts

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The Concept of Dysregulated Signal Transduction and Gene Expression in the Pathophysiology of Mood Disorders
Yogesh Dwivedi

Novel mechanistic concepts of the neurobiology of depression and bipolar disorder are evolving based on recent pre-clinical and clinical studies. Ongoing research could lead not only to a breakthrough in identifying the causative factors associated with mood disorders but also to the development of novel therapeutic interventions. One such recent breakthrough concerns the observed abnormalities in the two major signal transduction mechanisms most implicated in mood disorders: adenylyl-cyclase-cyclic adenosine monophosphate (AC-cAMP) and phosphoinositide (PI) hydrolysis. Among them are abnormalities in GTP binding proteins, phosphorylating enzymes, and substrate molecules observed in peripheral tissues and postmortem brain. More recently, cell survival pathways, such as the extracellular signal-regulated kinase and the Wnt pathways, which also cross-talk with AC-cAMP and PI signaling, have been investigated to elucidate their roles in the pathophysiology of mood disorders. Important consequences of the activation of these diverse signaling pathways are a modulation in the activation of transcription factors and, ultimately, in the regulation of gene expression. Particular attention is being paid to the roles of the transcription factor cAMP-response element binding protein and its target gene, brain-derived neurotrophic factor. Moreover, newer technologies, including complementary DNA microarray analysis, are revealing novel genes relevant to mood disorders. This critical overview presents our own and other groups' findings on various aspects of these signal transduction mechanisms, and on the regulation of gene expression, relevant to the pathophysiology of mood disorders.


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Is a “Mitochondrial Psychiatry” in the Future? A Review
Ann Gardner and Richard G. Boles

The field of “mitochondrial medicine” has advanced rapidly since the first patient with a mitochondrial disorder, a concept primarily used for defects of the respiratory chain, was described in 1962 and the first mitochondrial DNA (mtDNA) mutations were described in 1988. Because of the ubiquitous requirement for energy and unique aspects of mtDNA genetics, mtDNA mutations are known to cause a bewildering spectrum of clinical manifestations. However, because of its high-energy requirement, brain is the primary tissue affected in mitochondrial disorders. Using a variety of approaches, mitochondrial function has been shown in numerous studies to be abnormal in patients with schizophrenia and depression. Although less studied, an increase of psychiatric symptoms and disorders, in particular depression, are likely present in patients with mitochondrial disorders. The major categories of drugs used to treat schizophrenia and depression have been demonstrated to exert effects on mitochondria. The authors conclude that an association between energy metabolism and the mental disorders of schizophrenia and depression has been well documented, but that no conclusive evidence as yet demonstrates a causal relationship. A “mitochondrial psychiatry” model is proposed in which a moderate reduction in mitochondrial energy metabolism, genetically determined and/or acquired, is one predisposing factor in the multi-factorial development of certain chronic mental disorders. Clinical implications of our hypothesis, present and future, include the presence of co-morbid somatic symptoms/conditions, and specific treatment at least in highly-selected cases.


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Recent Developments in Deception Research
Catherine J. Hughes, Tom F.D. Farrow, Marie-Claire Hopwood, Angela Pratt, Michael D. Hunter and Sean A. Spence

Lying and deception are common human activities and may occur in a wide variety of clinical contexts. These behaviours implicate higher neural systems within the brains of humans and other primates. Recent functional neuroimaging studies suggest that prefrontal and anterior cingulate cortices are particularly engaged during certain forms of deception, hence, that executive processes support deceit. Congruent with the latter position is the finding that lies take longer to execute than truthful responses. To date, no functional neuroimaging study has demonstrated brain regions exhibiting greater activation during truth telling (compared with lying). Although the latter may reflect a Type II error, it also supports the hypothesis that truthfulness comprises a relative baseline in human cognition and communication. Those psychiatric disorders particularly associated with the practice of deception are varied both in aetiology and the degree to which deceit is central to their conceptualisation. Nevertheless, the deceiving human is likely to be engaging components of their cognitive executive system, a proposal with implications for societal notions of responsibility and mitigation. A successful lie denotes a functioning executive.


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Update on the Treatment of Pediatric Obsessive-Compulsive Disorder
Michael J. Larson, Eric A. Storch, Adam B. Lewin, Gary R. Geffken, Tanya K. Murphy and Wayne K. Goodman

Obsessive-compulsive disorder (OCD) is a debilitating disorder that is prevalent in pediatric populations. Due to the high prevalence and poor prognosis if left untreated, research into the effectiveness and efficacy of psychological and pharmacological treatments has expanded. Accompanying efforts to disseminate such treatments to practitioners has significantly lagged behind, resulting in many children and adolescents diagnosed with OCD not receiving appropriate treatment. This review discusses the current literature on pharmacological and psychological treatments of pediatric OCD, with emphasis on two empirically supported treatment modalities for children and adolescents: Cognitive-Behavioral Therapy (CBT) with exposure and response prevention (E/RP), and pharmacotherapy (serotonin reuptake inhibitors [SRIs] and selective serotonin reuptake inhibitors [SSRIs]). Discussion about the nature of these interventions, clinical challenges, and future areas for study are included.


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Antipsychotics in Obsessive-Compulsive Disorder
Giuseppe Maina, Umberto Albert, Enrico Pessina, Virginio Salvi and Filippo Bogetto

Drug treatment of OCD entails serotonin re-uptake inhibitors as first-line interventions. However, many patients with OCD do not benefit from standard treatments with SRIs; this proportion of patients may be approximately estimated between 40 and 50 percent of all subjects who are initially treated with these agents.
One of the most studied approaches for treatment-resistant patients is antipsychotic augmentation, which consists in adding to the ongoing SRI an antipsychotic. Good results have been obtained when the augmentation was made with a low-dose first generation antipsychotic (haloperidol, for which a double-blind study exists, and pimozide).

Given the side-effects profile of first generation antipsychotics, researchers have, in the last years, tried second generation ones as augmentation drugs. Risperidone, olanzapine and, more recently, quetiapine at low doses have been proved to be effective in a series of open label reports and in double-blind studies.

The present paper will review all available studies concerning the use of antipsychotics in OCD, pointing toward benefits and potential side effects of this augmentation strategy.

All of the studies that evaluated the addition of an antipsychotic in resistant OCD lasted 6-12 weeks; only a preliminary study lasted 16 weeks. A question that remains unresolved to date is then how long should a clinician maintain the antipsychotic augmentation in patients who responded to this strategy. In other words, is antipsychotic at low doses only necessary in order to elicit a response or is it also necessary in order to maintain it? Another way of looking at the problem is to examine whether the discontinuation of the antipsychotic in patients who responded to this strategy is associated with a worsening of obsessive-compulsive symptoms. We will present data on relapse rates in patients who responded to the addition of the antipsychotic and then discontinued it without discontinuing the SSRI.


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Towards an Integrated Clinical Psychobiology of Alcoholism
Colin R. Martin and Adrian B. Bonner

Alcohol dependency is a complex multi-factorial clinical presentation characterized by etiological ambiguity, poor treatment adherence and unfavorable prognosis. Recent evidence suggest considerable heterogeneity in this patient group across a number of neurological, genetic, psychological and personality parameters which relate directly to the clinical manifestation and course of this chronic condition. The current review examines contemporary cross-disciplinary research reports to present an integrated psychobiological synthesis of the main themes. The psychobiological model proposed offers a template for both clinicians and researchers to evaluate the relative contribution of key indicators to the end-point gestalt of alcohol dependency. Analysis and integration of psychobiological risk factors are illuminated within the context of sub-type identification, tailored treatment interventions and clinical outcome prediction. Implications for current psychiatric practice and the direction of future research are discussed.


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Transcription and Neurotrophic Factors in Affective Disorders: New Trends in Understanding the Action of Antidepressant Drugs
Francois P. Monnet

Apart from the well-known serotoninergic and noradrenergic receptors located at the plasma membrane, the pharmacological response to antidepressant drugs also includes the long term recruitment of nuclear transcription factors, such as CREB (AMPc response element binding protein), and neurotrophic factors such as BDNF (brain derived neurotrophic factor) that are also known to exhibit neuroprotective activities and participate in neuronal plasticity. The present review presents the most recent data on this topic, shedding new light on trends in the understanding of the neurobiology of affective disorders.


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Clinical Characteristics as Predictors of Response to Fluvoxamine, Paroxetine and Milnacipran in Patients with Depression
Shigeru Morishita and Seizabur Arita

The advent of the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin noradrenaline reuptake inhibitors (SNRIs) has been welcomed by patients, largely owing to their superior tolerability profile as compared to older antidepressants. However, individual SSRIs and SNRIs do not have the same effect on all patients all the time. The characteristics of fluvoxamine, paroxetine, and milnacipran used for the treatment of depression are reviewed in this paper. Fluvoxamine, paroxetine, and milnacipran each have their own optimal doses and appropriate treatment durations. Gender, age, first episode or recurrence, family history, psychiatric symptoms, and manic change rate were considered as predictors of the response to fluvoxamine, paroxetine, and milnacipran. Fluvoxamine showed a good response in young adults and in those with a first episode. Paroxetine showed a good response in first episode patients. Milnacipran showed a good response in older patients, males, first episode patients, and those with agitated depression. Paroxetine use was associated with a higher rate of mania induction than fluvoxamine and milnacipran. Knowing these characteristics should help guide clinicians in selecting antidepressants for their patients with depression.


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Bipolar Depression: The Neglected Realm of Postpartum Disorders
Verinder Sharma

Postpartum disorders include a spectrum of psychopathology including the postpartum blues, postpartum depression, and postpartum psychosis. Brief episodes of hypomania are quite common immediately after delivery but are rarely diagnosed. There is substantial evidence that postpartum psychosis is usually a variant of bipolar disorder in the form of a mixed or manic episode. Research studies however, have neglected the clinical reality that the postpartum period is also a high-risk time for the occurrence of episodes of bipolar depression. Diagnosing bipolar depression is not difficult in women with a history of a mixed or manic episode. However, misdiagnosis of bipolar II depression may be common after childbirth due to the likelihood that hypomania may be misconstrued as the normal joy related to the experience of motherhood. Early and accurate recognition of bipolar disorder is crucial as the use of antidepressants in patients with a bipolar diathesis can worsen the illness course due to induction of hypomanic, manic, and mixed episodes as well as acceleration of cycle frequency. This paper reviews the relationship between postpartum depression and bipolar disorder, and discusses the clinical and treatment implications of misdiagnosis of bipolar II depression as an episode of major depression.


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The Neurobiology of Love
Donatella Marazziti

In these last years, emotions and feelings, such as attachment, pair and parental bonding and even love, typical of higher mammals, neglected for centuries by experimental sciences, have become the topic of extensive neuroscientific research in order to elucidate their biological mechanisms. Several observations have highlighted the role of distinct neural pathways, as well as of monoamines and neuropeptides, in particular oxytocin, vasopressin and opiates, but this is only the beginning of the story.

Love, the most typical human feeling, can be viewed, according to a neurobiological perspective, as a dynamic process that represents the results of different components probably subserved by distinct neural substrates at different times. As such, some steps can be identified, in particular its beginning, that is to fall in love, which is the mechanism of attraction, followed by the stage of attachment, which, in some cases, can be lifelong.

This paper will review the available data regarding the process of attraction and attachment, and will draw some general speculations of the author, trying to address the question of what is love from a neurobiological point of view.


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Involvement of the Serotonergic System in Cognitive and Behavioral Symptoms of Alzheimer´s Disease
María Javier Ramírez, Bárbara Aisa, Francisco Javier Gil-Bea and Beatriz Marcos

Alzheimer’s disease (AD) is a chronic progressive disorder characterized by dementia, but often featuring behavioral and psychological syndromes (BPSD), such as depression, overactivity, psychosis or aggressive behavior. Traditional treatments for BPSD are neuroleptics and sedatives, which are not devoid of serious adverse effects. Neurochemically, the classical hallmark of AD is the disruption of basal forebrain cholinergic pathways and consequent cortical cholinergic denervation of the neocortex and hippocampus. However, it is conceivable that, according to the complexity and diversity of BPSD, more than one transmitter system may contribute to a particular behavioral syndrome. The serotonergic system has been implicated not only in cognitive processes, but also in depression, psychosis or aggression. In AD, extensive serotonergic denervation has been reported. In particular, there is growing interest in the pathological functions and implication in BPSD of 5-HT6 receptors, due to its high affinity for antipsychotic drugs and its distribution in the brain. In this study we will review the present knowledge of the involvement of the serotonergic system and its receptors in cognitive deficits and BPSD. From the currently available data, it is possible to conclude that pharmacological manipulation of serotonergic system may improve not only cognitive function but behavioral disturbances in dementia.


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Neurotransmitter Dysfunction and Neurotransmitter Replacement Therapy as Part of Frontotemporal Dementia Treatment
Martine Vercelletto, Michel Bourin, Lucette Lacomblez, Patrice Verpillat and Pascal Derkinderen

Very few studies on the neurotransmitter systems involved in frontotemporal dementia (FTD) have been published. No cholinergic deficiency is associated with FTD. Correlating non-specific, serotoninergic dysfunction and behavioral disorders permitted developing clinical trials on selective serotonin reuptake inhibitors (SSRIs). All five trials included a limited number of patients. Two preliminary trials involving the treatment of cognitive and attentional dysfunctions by noradrenergic agents were also developed on the hypothesis that noradrenergic system dysfunction was associated with FTD. Replacement neurotransmitter therapy to treat behavioral and cognitive symptoms in FTD has, however, proved disappointing so far. The pathophysiology of FTD is still poorly understood. Abnormalities linked to the tau protein level and excitotoxicity have been hypothesised. The most promising biological therapy would currently be to inhibit tau protein aggregation. Developing clinical trials on neuroprotective drugs will therefore require prior development of rating scales specific to this essentially behavioral type of dementia.