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Deep brain stimulation (DBS) is a reversible surgical procedure that involves stereotactic implantation of electrodes into the targeted brain regions, with a subcutaneously placed pulse generator powering the electrodes via one or two leads. The mechanism of action can be explained by the stimulation-induced modulation of impaired network activity. So far, the main use of DBS has been for neurological conditions, such as essential tremor, motor symptoms in Parkinson's disease, dystonia, epilepsy, and chronic pain. In psychiatry, case series and open studies indicate treatment efficacy of DBS in Gilles de la Tourette syndrome, treatment-resistant obsessive-compulsive disorder, and refractory major depression. Neuroimaging studies have confirmed the effects of DBS on the brain regions implicated in specific neuropsychiatric disorders. It is a well-tolerated method with relatively few serious side effects. Additional well-designed and appropriately powered controlled clinical trials are needed to conclusively establish the efficacy and safety of DBS and to identify the patient population(s) who may benefit most. Ongoing research with stimulation techniques may also significantly contribute to our understanding of major neuropsychiatric disorders.
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PMID:Deep brain stimulation in psychiatry. 1902 77

Within the recent development of brain-machine-interfaces deep brain stimulation (DBS) has become one of the most promising approaches for neuromodulation. After its introduction more than 20 years ago, it has in clinical routine become a successful tool for treating neurological disorders like Parkinson's disease, essential tremor and dystonia. Recent evidence also demonstrates efficacy in improving emotional and cognitive processing in obsessive-compulsive disorder and major depression, thus allowing new treatment options for treatment refractory psychiatric diseases, and even indicating future potential to enhance functioning in healthy subjects. We demonstrate here that DBS is neither intrinsically unethical for psychiatric indications nor for enhancement purposes. To gain normative orientation, the concept of "personality" is not useful--even if a naturalistic notion is employed. As an alternative, the common and widely accepted bioethical criteria of beneficence, non-maleficence, and autonomy allow a clinically applicable, highly differentiated context- and case-sensitive approach. Based on these criteria, an ethical analysis of empirical evidence from both DBS in movement disorders and DBS in psychiatric disease reveals that wide-spread use of DBS for psychiatric indications is currently not legitimated and that the basis for enhancement purposes is even more questionable. Nevertheless, both applications might serve as ethically legitimate, promising purposes in the future.
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PMID:Stimulating personality: ethical criteria for deep brain stimulation in psychiatric patients and for enhancement purposes. 1907 7

We examined the efficacy and tolerability of perospirone, a dopamine D2 and 5-HT2A receptor antagonist and a partial 5-HT1A receptor agonist, in the augmentation of antidepressant treatment of partially responding and nonresponding patients with major depressive disorder. Twelve patients with major depressive disorder and an incomplete or no response to different kinds of antidepressants (selective serotonin reuptake inhibitor, milnacipran, or sulpride) monotherapy or polytherapy for 8 weeks or more were treated with perospirone augmentation in an eight-week, open-label study. Data were gathered from July 2006 to March 2008. The mean duration of antidepressant pharmacotherapy at baseline was 28 weeks. At baseline, the mean (+/-SD) of the MADRS scores was 35.8+/-10.1. The mean (+/-SD) initial dose of perospirone was 7.0+/-2.9 mg/day and the final dose was 11.7+/-6.6 mg/day. Significant reductions in MADRS scores were observed at weeks 2, 4, 6 and 8. Although two of the twelve subjects who completed the protocol achieved remission by the study endpoint, five of the twelve patients were responders (i.e., >50% improvement in the MADRS score). Sleepiness and tremor were observed in six patients and one patient, respectively, resulting in a reduction of perospirone dose due to these side effects. The discontinuation rate after 8 weeks of treatment was zero. These findings suggest that perospirone may be an effective augmentation strategy for improving therapeutic response in patients with treatment-resistant major depressive disorder when administered in combination with standard antidepressant therapy. Based on this clinical evidence, a double-blind, placebo-controlled trial is warranted.
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PMID:Augmentation of antidepressants with perospirone for treatment-resistant major depressive disorder. 1916 96

Milnacipran is a dual-action antidepressant which inhibits both serotonin and norepinephrine reuptake. To our knowledge, it has limited affinity for most monoamine neurotransmitter receptors. With limited pharmacokinetic interaction with the cytochrome 450 system, milnacipran may have a low risk in drug interaction. The present study compares milnacipran with paroxetine, a selective serotonin reuptake inhibitor (SSRI) and which has been used clinically for years to evaluate the efficacy, patient tolerance, and side effects in the treatment of major depression. The study took place in two medical centers located in Northern and Southern Taiwan. Six-three participant who met the Diagnostic and Statistical Manual of Mental Disorder 4th edition (DSM-IV) criteria for a major depressive disorder and a total Hamilton Depression Rating Scale (HAM-D) score > or = 16 on the 17 item scale, were recruited. Participants first received either 100 mg/day of milnacipran (33 participants) or 20 mg/day of paroxetine (30 participants), and were then assessed with HAM-D and clinical global impression scale (CGI) for severity of the illness and global improvement, at the beginning and the end of the first, second, fourth, and eighth weeks of the drug treatment. Thirty-eight patients with major depressive disorder completed the study. No statistically significant differences were observed between the two groups in the reduction of HAM-D and CGI scores. However, side effects such as headache and tremor in the first week, psychomotor retardation and difficulty in concentration in the fourth week, and psychomotor retardation in the eighth week of treatment were significantly lower in the milnacipran group, as compared to that of the paroxetine group. We concluded that milnacipran and paroxetine had similar clinical effectiveness during the eight-week treatment of major depressive disorder. Further investigation is needed to examine the clinical suitability of this drug for patients with liver impairments and for elderly patients suffering from major depression.
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PMID:Lower side effects of milnacipran than paroxetine in the treatment of major depression disorder among Han Chinese in Taiwan. 1928 Aug 83

Major depression is an illness with objective physical signs occurring with some consistency. These signs are retardation of movements and diminished gestures and expressions. The patient may appear tired, self-concerned, bored, and inattentive and display a loss of interest in the surroundings. Anxiety is a conspicuous and an integral element of affective state and may be expressed by severe restlessness and agitation. Muscle tension, wringing of hands, weeping and moaning, repeating over and over in a monotonous and stereotyped way phrases expressive of misery are all important clinical signs of major depression. Similarly tachycardia, dry tongue/mouth, sweaty palms and/or bodily extremities, cold clammy skin, pallor, pupillary dilatation, tremor, and the fluctuations in blood pressure with wide pulse pressure are all important and give away the underlying distress. These signs have formed an integral part of both the Hamilton Depression Rating Scale and the Montgomery-Asberg Depression Rating Scale as they have a positive correlation with the diagnosis and the severity of illness. Current practice of operational criteria does not help exclude patients with subjective perception of distress and also fails to make room for aetiopathogenesis. The DSM-IV does not include these physical signs as an integral part of the clinical picture of depression, consequently leaving the diagnosis of MDE to subjective criteria and perceptions. This could also explain a large placebo response in recent randomised controlled clinical trials.
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PMID:Major depression: an illness with objective physical signs. 1962 57

ABSTRACT Fifteen adolescents and young adults (ages 16-24) with a DSM-III-R diagnosis of major depression, who failed to respond to prior treatment with tricyclic antidepressants, were treated in an open trial using fluoxetine. Of the 11 patients who completed a 6-7 week trial, 64% showed a therapeutic response (>/=50% change) on the Hamilton Depression Rating Scale (HDRS), and 73% showed a positive response when rated by the Clinical Global Impression Scale (CGI). Side effects generally were mild, and the most common were tremor, dry mouth, nausea, sweating, and decreased appetite. Sweating, drowsiness, dry mouth, tremor, and alopecia appeared more commonly than in adult studies. One patient became manic, and none showed an increase in suicidal ideation. A starting dose of 20 mg daily often was tolerated poorly, and patients generally did better with 5-10 mg daily for the first week. Some patients appeared to exhibit antidepressant responses on 5-10 mg daily. These preliminary data suggest that fluoxetine, in doses ranging from 5 to 40 mg daily, when used in combination with psychosocial treatments, may be an effective antidepressant in adolescents or young adults who have not previously responded to adequate tricyclic therapy. Double-blind placebo-controlled studies are needed to evaluate the potential efficacy of fluoxetine in treating major depression in adolescents and young adults.
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PMID:An open naturalistic trial of fluoxetine in adolescents and young adults with treatment-resistant major depression. 1963 Jun 47

Bupropion, a noradrenaline/dopamine reuptake inhibitor, and venlafaxine, a serotonin/noradrenaline reuptake inhibitor, are both established antidepressants with proven efficacy in randomized controlled clinical trials. The objective of this double-blind, randomized, placebo- and active-controlled, eight-week, flexible-dose study was to evaluate the efficacy and tolerability of the once-daily extended-release formulations of these two antidepressants compared with placebo. Patients with major depressive disorder were randomized to once-daily treatment with bupropion XR 150 mg (n = 204), the extended-release formulation of venlafaxine (venlafaxine XR) 75 mg (n = 198) or placebo (n = 189) during weeks 1 to 4, with the option to double the dose at week 5 if response was inadequate. In this study, bupropion XR did not demonstrate statistically significant evidence of greater improvement from baseline compared with placebo on week 8 Montgomery Asberg Depression Rating scale scores (primary endpoint) or on secondary endpoints including CGI, HAM-A and responder and remitter analyses. Descriptive statistics for venlafaxine XR indicated separation versus placebo on MADRS total scores at week 8 and other intermediate time points, and on other endpoints including CGI, HAM-A and responder and remitter analyses. Both active treatments elicited improvement on the Sheehan Disability Scale and its subscales and were generally well tolerated at the doses studied. Rates of nausea, dry mouth, dizziness, hyperhidrosis, insomnia, constipation, tremor, anorexia and male sexual dysfunction were elevated in the venlafaxine XR group, consistent with its mixed serotonergic/noradrenergic mechanism. Rates of dry mouth, insomnia and hyperhidrosis were elevated in the bupropion XR group, consistent with its catecholaminergic mechanism.
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PMID:Double-blind, placebo-controlled comparison of the antidepressant efficacy and tolerability of bupropion XR and venlafaxine XR. 1993 70

To accomplish therapeutic goal it is necessary to adjust the dose of medication to be right for every single patient. This procedure of dose adjustment is individualized dose regimen. First of all, pharmacokinetic aspects should be revised, including parameters such as resorption, distribution, metabolism and secretion of drug. For these purposes, the authors developed and clinically assessed the modified Bayesian method supported by original basic computer program. The aim of research was to compare frequency of adverse events in cases of individualized and empiric dose regimens of amitriptyline in the treatment of major depressive episode. Sixty subjects (32- 65 years old), with major depressive disorder (International Classification of Disease, 10th revision), were randomly assigned and single- blinded to take individualized (experimental group, n=30) or empiric (control group, n=30) doses of amitriptyline for 8 weeks. CGI scale and originally designed questionnaire were used for adverse events assessment. In experimental group, 69 complaints on nine different types of adverse effects were recorded during eight-week treatment period. Severe adverse events, such as confusion or arrhythmia, were not registered in this subgroup. In control group, 111 complaints on twelve different types of adverse effects were recorded. Most common were anticholinergic effects, but during the third and fourth week from baseline, some severe adverse events were observed: tremor (16%), fatigue (16%), in one of the subjects confusion occurred and arrhythmia in another. Analyzing of the results according to CGI scale for adverse events showed that, during the treatment period, adverse events were less frequent in experimental group. This was particularly obvious in the first four weeks of treatment, when statistically significant difference (p<0.05) was observed.
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PMID:Comparison of safety between individualized and empiric dose regimen of amitriptyline in the treatment of major depressive episode. 2056 81

Deep brain stimulation (DBS) of the globus pallidus interna and subthalamic nucleus has restored some degree of motor control in many patients in advanced stages of Parkinson's disease. DBS has also been used to treat dystonia, essential tremor (progressive neurological condition causing trembling), chronic pain, obsessive-compulsive disorder, Tourette's syndrome, major depressive disorder, obesity, cerebral palsy, and the minimally conscious state. Although the underlying mechanisms of the technique are still not clear, DBS can modulate underactive or overactive neural circuits and restore disrupted communication between and among groups of neurons in interacting regions of the brain.This can control and relieve many symptoms associated with a range of neurological and psychiatric disorders. But the procedures of implanting and stimulating the electrodes are brain-invasive and entail significant risks. Some patients receiving DBS have experienced intracerebral hemorrhage, infection, cognitive disturbances such as impulsive behavior, and affective disturbances such as mania. It is not known whether continuous electrical stimulation of the brain would reshape synaptic connectivity and permanently alter neural circuits in ways that may not be salutary. The risk of these effects indicates that DBS should be used only when a patient's condition is refractory to all other interventions and when there is a high probability that the technique will benefit the patient and improve his or her quality of life. If a patient's quality of life is poor and all other treatment options have been exhausted, then the likelihood of benefit can justify physicians' exposing patients to some risk. The clinical and ethical significance of the risk in DBS underscores the obligation of physicians to obtain fully informed consent from patients undergoing the procedure.
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PMID:Consent to deep brain stimulation for neurological and psychiatric disorders. 2086 16

Deep brain stimulation (DBS) is a clinically established procedure for treating severe motor symptoms in patients suffering from end-stage Parkinson's disease, dystonia and essential tremor. Currently, it is tested for further indications including psychiatric disorders like major depression and a variety of other diseases. However, ethical issues of DBS demand continuing discussion. Analysing neuroethical and clinical literature, five major topics concerning the ethics of DBS in clinical practice were identified: thorough examination and weighing of risks and benefits; selecting patients fairly; protecting the health of children in paediatric DBS; special issues concerning patients' autonomy; and the normative impact of quality of life measurements. In exploring DBS for further applications, additionally, issues of research ethics have to be considered. Of special importance in this context are questions such as what additional value is generated by the research, how to realise scientific validity, which patients should be included, and how to achieve an acceptable risk-benefit ratio. Patients' benefit is central for ethical evaluation. This criterion can outweigh very serious side-effects, and can make DBS appropriate even in paediatrics. Because standard test procedures evade central aspects of patients' benefits, measuring quality of life should be supplemented by open in-depth interviews to provide a more adequate picture of patients' post-surgical situation. To examine its entire therapeutic potential, further research in DBS is needed. Studies should be based on solid scientific hypotheses and proceed cautiously to benefit severely suffering patients without putting them to undue risks.
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PMID:Ethical brain stimulation - neuroethics of deep brain stimulation in research and clinical practice. 2103 55


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