The integrative management of treatment-resistant depression: a comprehensive review and perspectives.

Major depressive disorder is a prevalent and disabling illness. Notwithstanding numerous advances in the pharmacological treatment of depression, approximately 70% of patients do not remit after first-line antidepressant treatment.

Revisiting the monoamine hypothesis of depression: a new perspective.

As the incidence of depression increases, depression continues to inflict additional suffering to individuals and societies and better therapies are needed. Based on magnetic resonance spectroscopy and laboratory findings, gamma aminobutyric acid (GABA) may be intimately involved in the pathophysiology of depression. The isoelectric point of GABA (pI = 7.3) closely approximates the pH of cerebral spinal fluid (CSF). This may not be a trivial observation as it may explain preliminary spectrophotometric, enzymatic, and HPLC data that monoamine oxidase (MAO) deaminates GABA. Although MAO is known to deaminate substrates such as catecholamines, indoleamines, and long chain aliphatic amines all of which contain a lipophilic moiety, there is very good evidence to predict that a low concentration of a very lipophilic microspecies of GABA is present when GABA pI = pH as in the CSF. Inhibiting deamination of this microspecies of GABA could explain the well-established successful treatment of refractory depression with MAO inhibitors (MAOI) when other antidepressants that target exclusively levels of monoamines fail. If further experimental work can confirm these preliminary findings, physicians may consider revisiting the use of MAOI for the treatment of non-intractable depression because the potential benefits of increasing GABA as well as the monoamines may outweigh the risks associated with MAOI therapy.

Emotion recognition from dynamic emotional displays following anterior cingulotomy and anterior capsulotomy for chronic depression

Four patients that had received an anterior cingulotomy (ACING) and five patients that had received both an ACING and an anterior capsulotomy (ACAPS) as an intervention for chronic, treatment refractory depression were presented with a series of dynamic emotional stimuli and invited to identify the emotion portrayed. Their performance was compared with that of a group of non-surgically treated patients with major depression (n = 17) and with a group of matched, never-depressed controls (n = 22). At the time of testing, four of the nine neurosurgery patients had recovered from their depressive episode, whereas five remained depressed. Analysis of emotion recognition accuracy revealed no significant differences between depressed and non-depressed neurosurgically treated patients. Similarly, no significant differences were observed between the patients treated with ACING alone and those treated with both ACING and ACAPS. Comparison of the emotion recognition accuracy of the neurosurgically treated patients and the depressed and healthy control groups revealed that the surgically treated patients exhibited a general impairment in their recognition accuracy compared to healthy controls. Regression analysis revealed that participants' emotion recognition accuracy was predicted by the number of errors they made on the Stroop colour-naming task. It is plausible that the observed deficit in emotion recognition accuracy was a consequence of impaired attentional control, which may have been a result of the surgical lesions to the anterior cingulate cortex. © 2007 Elsevier Ltd. All rights reserved.

Clinical trial design in non-invasive brain stimulation psychiatric research

Major depressive disorder (MDD) trials - investigating either non-pharmacological or pharmacological interventions - have shown mixed results. Many reasons explain this heterogeneity, but one that stands out is the trial design due to specific challenges in the field. We aimed therefore to review the methodology of non-invasive brain stimulation (NIBS) trials and provide a framework to improve clinical trial design. We performed a systematic review for randomized, controlled MDD trials whose intervention was transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in MEDLINE and other databases from April 2002 to April 2008. We created an unstructured checklist based on CONSORT guidelines to extract items such as power analysis, sham method, blinding assessment, allocation concealment, operational criteria used for MDD, definition of refractory depression and primary study hypotheses. Thirty-one studies were included. We found that the main methodological issues can be divided in to three groups: (1) issues related to phase II/small trials, (2) issues related to MDD trials and, (3) specific issues of NIBS studies. Taken together, they can threaten study validity and lead to inconclusive results. Feasible solutions include: estimating the sample size a priori; measuring the degree of refractoriness of the subjects; specifying the primary hypothesis and statistical tests; controlling predictor variables through stratification randomization methods or using strict eligibility criteria; adjusting the study design to the target population; using adaptive designs and exploring NIBS efficacy employing biological markers. In conclusion, our study summarizes the main methodological issues of NIBS trials and proposes a number of alternatives to manage them. Copyright (C) 2011 John Wiley & Sons, Ltd.

How much is too much? Oligosymptomatic presentation after 11.5 g of diphenhydramine

We report the case of a 47-year-old male obese Caucasian patient presenting 2 hours after ingestion of 11.5 g of diphenhydramine. Despite this excessive overdose, he showed only a few hours of impaired consciousness and no further symptoms. A diphenhydramine plasma concentration of 15,352 nmol/L was measured 8 hours after the overdose ingestion. A heterogeneous CYP2D6 extensive metabolizer genotype excludes a pharmacokinetic explanation for this unusually oligosymptomatic presentation. However, the patient suffered from longstanding, refractory depression despite numerous treatment attempts with various drugs, pointing to the possibility of decreased pharmacodynamic responsiveness for therapeutic and toxic effects.

Repetitive transcranial magnetic stimulation activates specific regions in rat brain

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique to induce electric currents in the brain. Although rTMS is being evaluated as a possible alternative to electroconvulsive therapy for the treatment of refractory depression, little is known about the pattern of activation induced in the brain by rTMS. We have compared immediate early gene expression in rat brain after rTMS and electroconvulsive stimulation, a well-established animal model for electroconvulsive therapy. Our result shows that rTMS applied in conditions effective in animal models of depression induces different patterns of immediate-early gene expression than does electroconvulsive stimulation. In particular, rTMS evokes strong neural responses in the paraventricular nucleus of the thalamus (PVT) and in other regions involved in the regulation of circadian rhythms. The response in PVT is independent of the orientation of the stimulation probe relative to the head. Part of this response is likely because of direct activation, as repetitive magnetic stimulation also activates PVT neurons in brain slices.

Antidepressant specificity of serotonin transporter suggested by three LeuT-SSRI structures.

Sertraline and fluoxetine are selective serotonin re-uptake inhibitors (SSRIs) that are widely prescribed to treat depression. They exert their effects by inhibiting the presynaptic plasma membrane serotonin transporter (SERT). All SSRIs possess halogen atoms at specific positions, which are key determinants for the drugs' specificity for SERT. For the SERT protein, however, the structural basis of its specificity for SSRIs is poorly understood. Here we report the crystal structures of LeuT, a bacterial SERT homolog, in complex with sertraline, R-fluoxetine or S-fluoxetine. The SSRI halogens all bind to exactly the same pocket within LeuT. Mutation at this halogen-binding pocket (HBP) in SERT markedly reduces the transporter's affinity for SSRIs but not for tricyclic antidepressants. Conversely, when the only nonconserved HBP residue in both norepinephrine and dopamine transporters is mutated into that found in SERT, their affinities for all the three SSRIs increase uniformly. Thus, the specificity of SERT for SSRIs is dependent largely on interaction of the drug halogens with the protein's HBP.

SSRI administration reduces resting state functional connectivity in dorso-medial prefrontal cortex

Recent evidence suggests that an area in the dorsal medial prefrontal cortex (dorsal nexus) shows dramatic increases in connectivity across a network of brain regions in depressed patients during the resting state;1 this increase in connectivity is suggested to represent hotwiring of areas involved in disparate cognitive and emotional functions.1, 2, 3 Sheline et al.1 concluded that antidepressant action may involve normalisation of the elevated resting state functional connectivity seen in depressed patients. However, the effects of conventional pharmacotherapy for depression on this resting state functional connectivity is not known and the effects of antidepressant treatment in depressed patients may be confounded by change in symptoms following treatment.

Depression in temporal lobe epilepsy surgery patients : an FDG-PET study

Summary: Purpose: Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery.

Methods: We studied 23 medically refractory TLE patients who underwent anterior temporal lobectomy and who had preoperative FDG-PET scanning. All patients had pre- and postoperative psychiatric assessment. By using statistical parametric mapping (SPM-99), patterns of hypometabolism were compared between patients who had a preoperative history of depression (n = 9) versus those who did not (n = 14) and between those in whom postoperative depression developed (n = 13) versus those in whom it did not (n = 10). A significant region of hypometabolism was set at p < 0.001 for a cluster of ≥20 contiguous voxels.

Results: Patients with a history of depression at any time preoperatively showed focal hypometabolism in ipsilateral orbitofrontal cortex compared with those who did not (t= 4.64; p < 0.001). Patients in whom depression developed postoperatively also showed hypometabolism in the ipsilateral orbitofrontal region (t= 5.10; p < 0.001).

Conclusions: Although this study is methodologically limited, and other explanations merit consideration, orbitofrontal cortex dysfunction, already implicated in the pathophysiology of nonepileptic depression, may also be relevant to the depression of TLE and temporal lobectomy.

Disrupting disordered neurocircuitry : treating refractory psychiatric illness with neuromodulation

Despite the premature and somewhat infamous rise and fall of psychosurgery in the mid-20th century, the current era of functional neuromodulation proffers immense opportunity for surgical intervention in treatment-resistant psychiatric disorders. On the basis of recent successes with novel, focused, less invasive, and reversible treatment strategies for movement disorders, several therapeutic trials have been conducted to investigate the effectiveness of deep brain stimulation (DBS) in treatment-resistant depression, obsessive-compulsive disorder (OCD), and Tourette syndrome. The many anatomic targets for these psychiatric disorders are indicative of both the system-wide effects of DBS and the network-level dysfunction mediating the emotional and cognitive disturbances. To gain insight into the application of neuromodulation therapies and their further advancement, we must elucidate neuroanatomic networks involved in refractory psychiatric illness, the neurophysiological anomalies that contribute to disordered information processing therein, and the local and system-wide modulatory effects of DBS. This review discusses the history of psychosurgical procedures, recent DBS clinical data, current anatomic models of psychopathology, and possible therapeutic mechanisms of action of DBS neuromodulation. Our search criteria for PubMed included combinations of the following terms: neuromodulation, DBS, depression, OCD, Tourette syndrome, mechanism of action, and history. Dates were not restricted. As clinical and basic scientific investigations probe the neuromodulatory effects of DBS in the treatment of refractory neuropsychiatric illness, our knowledge of these disorders and our potential to treat them are rapidly expanding. Indeed, this modern era of neuromodulation may provide the key that unlocks many of the mysteries pertaining to the biological basis of disordered emotional neurocircuitry.

Application of the gradient boosted method in randomised clinical trials: participant variables that contribute to depression treatment efficacy of duloxetine, SSRIs or placebo

Randomised, placebo-controlled trials of treatments for depression typically collect outcomes data but traditionally only analyse data to demonstrate efficacy and safety. Additional post-hoc statistical techniques may reveal important insights about treatment variables useful when considering inter-individual differences amongst depressed patients. This paper aims to examine the Gradient Boosted Model (GBM), a statistical technique that uses regression tree analyses and can be applied to clinical trial data to identify and measure variables that may influence treatment outcomes.

Psychiatric comorbidity in refractory focal epilepsy: A study of 490 patients

We studied the prevalence and associated factors of psychiatric comorbidities in 490 patients with refractory focal epilepsy. Of these, 198 (40.4%) patients had psychiatric comorbidity. An Axis I diagnosis was made in 154 patients (31.4%) and an Axis II diagnosis (personality disorder) in another 44 (8.97%) patients. After logistic regression, positive family history of psychiatric comorbidities (O.R.=1.98; 95% CI=1.10-3.58; p=0.023), the presence of Axis II psychiatric comorbidities (O.R.=3.25; 95% CI=1.70-6.22; p<0.0001), and the epileptogenic zone located in mesial temporal lobe structures (O.R.=1.94; 95% CI=1.25-3.03; p=0.003) remained associated with Axis I psychiatric comorbidities. We concluded that a combination of clinical variables and selected structural abnormalities of the central nervous system contributes to the development of psychiatric comorbidities in patients with focal epilepsy. (C) 2012 Published by Elsevier Inc.

Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease

The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis.