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Clinical utility of commercial multi-gene pharmacogenetic tests in depression is starting to be studied with some promising results on efficacy and tolerability. Among the next steps is the definition of the patient profile that is most likely to benefit from testing. Here we present a reanalysis of data from the AB-GEN randomized clinical trial showing that clinical utility of pharmacogenetic testing can be markedly influenced by patient characteristics such as age, baseline severity and duration of current depressive episode. Trial registration ClinicalTrials.gov NCT02529462.

BACKGROUND AND PURPOSE The antidepressant efficacy of selective 5-HT reuptake inhibitors (SSRI) and other 5-HT-enhancing drugs is compromised by a negative feedback mechanism involving 5-HT1A autoreceptor activation by the excess 5-HT produced by these drugs in the somatodendritic region of 5-HT neurones. 5-HT1A receptor antagonists augment antidepressant-like effects in rodents by preventing this negative feedback, and the mixed β-adrenoceptor/5-HT1A receptor antagonist pindolol improves clinical antidepressant effects by preferentially interacting with 5-HT1A autoreceptors. However, it is unclear whether 5-HT1A receptor antagonists not discriminating between pre- and post-synaptic 5-HT1A receptors would be clinically effective. EXPERIMENTAL APPROACH We characterized the pharmacological properties of the 5-HT1A receptor antagonist DU-125530 using receptor autoradiography, intracerebral microdialysis and electrophysiological recordings. Its capacity to accelerate/enhance the clinical effects of fluoxetine was assessed in a double-blind, randomized, 6 week placebo-controlled trial in 50 patients with major depression (clinicaltrials.gov identifier NCT01119430). KEY RESULTS DU-125530 showed equal (low nM) potency to displace agonist and antagonist binding to pre- and post-synaptic 5-HT1A receptors in rat and human brain. It antagonized suppression of 5-hydroxytryptaminergic activity evoked by 8-OH-DPAT and SSRIs in vivo. DU-125530 augmented SSRI-induced increases in extracellular 5-HT as effectively as in mice lacking 5-HT1A receptors, indicating a silent, maximal occupancy of pre-synaptic 5-HT1A receptors at the dose used. However, DU-125530 addition to fluoxetine did not accelerate nor augment its antidepressant effects. CONCLUSIONS AND IMPLICATIONS DU-125530 is an excellent pre- and post-synaptic 5-HT1A receptor antagonist. However, blockade of post-synaptic 5- HT1A receptors by DU-125530 cancels benefits obtained by enhancing pre-synaptic 5-hydroxytryptaminergic function.

Different reports suggest the estrogens are involved in neuritic outgrowth, maintenance of dendritic morphology and spine formation in the CNS. However, the molecular mechanisms regulated by estrogens on neuronal integrity are not fully understood. We have addressed the relationship between 17beta-estradiol-dependent ERK pathway stimulation and the maintenance of neuritic morphology in cerebellar granule cell cultures (CGC). We report that 17beta-estradiol clearly activates ERK phosphorylation in CGC cultured in low potassium via ERalpha localized in the plasma membrane and without the activation of the insulin-like growth factor-I receptor. 17beta-estradiol activates the ERK pathway through Ras-dependent Src kinase activity. A concomitant activation of the cAMP-response element-binding protein (CREB) is observed. Moreover, we demonstrate that 17beta-estradiol-mediated ERK activation is involved in the maintenance of neuritic arborisation and neuronal morphology in proapoptotic conditions.

IntroductionAlthough physical restraint (PR) is a non-rarely practice on psychiatry there are few studies that focus the attention on the risk factors for this intervention. PR is a legitimacy practice when is needed and well applied but is not free from side effects. Knowing risk factors might be useful to improve the application of PR.ObjectivesStudy the risk factors involved with the use of PR at patient's home in individuals with schizophrenia before the involuntary transport (IT) to a psychiatric facility.MethodsIs a descriptive and observational study of 267 psychotic patients that were assisted by a psychiatric home care unit (EMSE) in Barcelona during their IT. The sample was divided in two groups, depending on the need of PR. Socio-demographic data were collected as well as positive and negative syndrome scale (PANSS), WHO disability assessment schedule (WHO/DAS), global assessment of functioning scale (GAF), Scale to assess unawareness of mental disorder (SUMD). Aggressiveness was assessed by PANSS-EC consisting of 5 items: excitement, tension, hostility, uncooperativeness and poor impulse.ResultsFrom the 267 psychotic patients 109 required PR. 154 were male and the average of age was 47. The results were significant in the PR group versus no PR for PANSS-EC (P = 0.000), as well as WHO/DAS (P = 0.017), GAF (P = 0.042), Positive PANSS (P = 0.000), age (P = 0.001) and substance use (P = 0.012). Were no significant for gender, insight or Negative PANSS.ConclusionsAggressiveness and violence were the most important PR related factors followed by positive symptoms, age, substance use and global functioning.Disclosure of interestThe authors have not supplied their declaration of competing interest.

IntroductionConsultation-liaison (CL) psychiatry is a branch of psychiatry that study and treat mental health of patients with other medical or surgical conditions. The assistance between hospitals and health services is heterogeneous.Aims and objectivesFor this reason, the objective of our research is to define the clinical characteristics from our CL service and check out the quality relationship with the applicant service, for improving future assistance.MethodsWe made a descriptive analysis of clinical variables from the patients who received assistance during 2 months by the CL service from the hospital del Mar, Barcelona. We got the frequencies and we used the Chi2 test for the comparison between variables: Diagnosis, appearance in the report and treatment in the report.ResultsTotal of the sample: 42 patients, 61.9% women. Mean age: 55.1 years. Psychiatric diagnosis was present before the assistance on 57.1% of the patients. The most frequent diagnosis was Adjustment Disorder (47.6%) and more than one diagnosis was made in the 14.3%. Near the half of the patients required only primary care assistance after the discharge from the hospital. In the 68.3% of the reports appeared information about CL assistance and the indicated treatment didn’t appear in all the reports. Statistically significant differences weren’t found in the comparisons.ConclusionsAdjustment Disorder is supposed to be the most common psychiatric diagnosis in our CL psychiatry service, as we found in the reviewed literature. The results reveal that relationships between services can be improved. More studies must be done for completing information in this issue.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The present study examined the effect of the highly potent and selective MAO B inhibitor PF9601N on L-DOPA-induced rotational behavior in unilateral nigrostriatal 6-hydroxydopamine lesioned rats. Three doses of PF9601N (20, 40 and 60mg/kg) were administered 30 min before an injection of L-DOPA (25mg/kg), and both contralateral and ipsilateral rotational behavior was measured. In addition, we also studied the effect produced by another MAO B inhibitor, deprenyl (20mg/kg), the MAO A inhibitor, clorgyline (20mg/kg), and the dopamine reuptake inhibitor, GBR2909 (7.5 mg/kg) on L-DOPA-induced rotational behavior. The results showed that PF9601N plus L-DOPA significantly enhanced the duration of contralateral rotational behavior with respect to L-DOPA plus vehicle in a dose-related manner. At the dose of 40 and 60mg/kg, PF9601N produced significantly more overall contralateral turning than L-DOPA plus vehicle, and at the dose of 60mg/kg, PF9601N produced significantly more turning behavior than L-DOPA plus deprenyl. These results suggest that PF9601N may be used as a novel tool in the treatment of Parkinson's disease.

1. Previous studies with indolyl derivatives as monoamine oxidase (MAO) inhibitors have shown the relevance of the indole structure for recognition by the active site of this enzyme. We now report a new series of molecules with structural features which determine the selectivity of MAO inhibition. 2. A benzyloxy group attached at position 5 of the indole ring is critical for this selective behaviour. Amongst all of these benzyloxy-indolyl methylamines, N-(2-propynyl)-2-(5-benzyloxyindol)methylamine FA-73 was the most potent MAO-B 'suicide' inhibitor studied. 3. The Ki values for MAO-A and MAO-B were 800+/-60 and 0.75+/-0.15 nM, respectively. These data represent a selectivity value of 1066 for MAO-B, being 48 times more selective than L-deprenyl (Ki values of 376+/-0.032 and 16.8+/-0.1 nM for MAO A and MAO-B, respectively). The IC50 values for dopamine uptake in striatal synaptosomal fractions from rats were 150+/-8 microM for FA-73 and 68 +/- 10 microM for L-deprenyl whereas in human caudate tissue the IC50 values were 0.36+/-0.015 microM for FA-73 and 0.10+/-0.007 microM for L-deprenyl. Moreover, mouse brain MAO-B activity was 90% ex vivo inhibited by both compounds 1 h after 4 mg kg(-1) administration, MAO-A activity was not affected. 4. These novel molecules should provide a better understanding of the active site of monoamine oxidase and could be the starting point for the design of further selective, non-amphetamine-like MAO-B inhibitors with therapeutic potential for the treatment of neurological disorders.

A novel series of previously synthesised 2-[(5-methoxy-l-methylindolyl)]alkylamine derivatives were irreversible and time-dependent mechanism-based inhibitors of MAO. The effect of branching and elongation of the side chain was evaluated on the inhibitory potency towards MAO-A and MAO-B activities. The K1 of the reversible step and the kinact of the irreversible one were determined in each case. The results obtained lead to the conclusion that neither the elongation nor the branching of the side chain improve the potency of the compounds as MAO inhibitors.

IntroductionSeveral studies have suggested variations in the prevalence of schizophrenia spectrum disorders diagnosis across time. This could be due to a change in diagnostic practice motivated either for changes in DSM criteria as for local culture factors. The aim of this study is to explore the evolution of the schizophrenia spectrum disorders. We hypothesize that we would observe a transference from the schizophrenia diagnosis to psychosis not otherwise specified.MethodsA retrospective review of all psychiatric discharges in acute unit in the INAD of Parc de Salut Mar of Barcelona, between 2002 and 2014 was performed, relating each discharge to its axis I psychiatric diagnostic. An ANOVA analysis was used to calculate the differences between the months and the frequency of the diagnosis.ConclusionWe have not been able to observe any transference between diagnoses across years. We observe a decrease of the proportion of schizophrenic spectrum disorders in its prevalence at discharge from 2012 to 2014. The proportion of not otherwise specified psychosis remains quite constant as a third of the schizophrenia diagnoses.Disclosure of interestThe authors report no conflict of interest in this study. LG is funded by the Instituto.de.Salud.Carlos.III (CM14/00111).

IntroductionSocial withdrawal is a major health problem that has been related with higher morbidity and mortality rates. There are few studies about the relationship between suicidal behavior and social isolation.AimTo describe the existence of suicidal risk in subjects with social isolation.MethodParticipants were 187 subjects referred to a Crisis Resolution Home Treatment because of social isolation. The inclusion criteria were: home isolation, avoiding of social situations and relationships, for at least 6 months. Suicide risk was assessed by the item of the Severity of Psychiatric Illness, dividing in four groups (from absence to high suicide risk). Socio-demographic and clinical data were also analysed.ResultsMost cases (n = 132, 70.5%) had absence of suicide risk. They were predominantly young males in all groups. There were no statistically significant differences in sociodemographic or clinical variables. The mean age at onset of social isolation was lower in the high suicide risk group, having lower socially withdrawn period. This group had also lower rates of child abuse and suicide attempt history. The more frequent diagnosis in all groups was psychotic, affective and anxiety disorders. Those cases with mild and high suicide risk needed more frequently hospitalization.ConclusionsSocial isolated people attended by CRHT do not have high frequency of suicide risk. Cases with higher suicide risk are younger and have a shorter period of isolation. The absence of child abuse history or previous suicide attempts contrasts with previous suicidal behavior research. These data can be influenced by the characteristics of functioning of CRHT and the small sample size.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Effects of the parkinsonism inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopamine metabolism and the influence of sex on the recovery were investigated in adult (2-month-old) male and female C57/BL mice. We present here evidence that MPTP treatment (2 doses of 30 mg/kg i.p., each at 24 h interval) produced a similar reduction (-65% to -70%) of striatal dopamine in both sexes 24 h after the last injection of MPTP, and a greater loss of the metabolites in the female group. In contrast to the partial recovery observed in the male group, an increased dopamine loss occurred in the female group within 10 days following the last injection of MPTP. This impairment in recovery appears to be different to the one already observed in aged (24-month-old) male mice treated in similar conditions. As the neurotoxic effects of MPTP depend on its conversion to the 1-methyl-4-phenylpyridinium ion (MPP+) by monoamine oxidase B (MAO B), the presence of a different peripheral or central MAO B type in female mice could be in part responsible for these sex related effects. To investigate this possibility, MAO A and B activities were characterized in liver and brain of adult female control mice during the different steps of the oestrous cycle and compared to those of adult control male mice. Significant differences in MAO A and MAO B activities could be detected during the oestrous cycle and between the adult male and female groups. It is concluded that MAO B may be involved in the sex related effects of MPTP.

Interactions between some novel and potent monoamine oxidase inhibitors (MAOIs), acetylenic analogues of tryptamine, and rat liver microsomal cytochrome P450 (P450) as evidenced by visible spectra analysis were analysed. Compounds with a secondary aliphatic amine moiety throughout induced type II difference spectra and exhibited the highest affinity for P450, whereas tertiary amines induced type I spectral changes and showed diminished affinity. P450 dependent aniline hydroxylase activity was inhibited by all compounds in an irreversible time-dependent manner. Only tertiary aliphatic amines constituted the substrate for P450-dependent N-demethylase activity, with comparable kinetic parameters. The N-demethylated metabolites were identified by thin-layer chromatography and mass-spectrometric analyses. These findings describe the role of P450-dependent microsomal mono-oxygenase systems in the metabolism of some MAOI acetylenic tryptamine derivatives and the possible hepatic contribution to adverse interactions between MAOIs, endobiotics and sympathomimetic compounds.

Parkinson's disease is a motor and cognitive disorder characterised by a progressive loss of the substantia nigra pars compacta (SNc) dopaminergic neurons as well as of the locus coeruleus (LC) noradrenergic neurons. It has been suggested that LC neurodegeneration might influence levodopa-induced motor disturbances and cognitive performance. We investigated the influence of dopaminergic and noradrenergic lesions on levodopa-induced dyskinesias and on working memory in rats. Two groups of animals were used: (1) rats with a dopaminergic lesion induced by a unilateral administration of the neurotoxin 6-hydroxydopamine (6-OHDA), and (2) rats with a combined lesion of the dopaminergic and noradrenergic systems induced by 6-OHDA and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), respectively. Dyskinesias were evaluated on days 1, 8, 15 and 22 of chronic levodopa treatment (6 mg/kg, twice at day, i.p.). Working memory was evaluated by a radial-arm maze (1) before lesions, (2) before levodopa administration and (3) after 22 days of levodopa treatment. Total, axial, limb and orofacial dyskinesias not differed significantly between both groups. Working memory tasks worsened in both lesioned groups reaching significance in terms of time of performance (P < 0.05). The number of repeated entries in the same arm (errors) was only significant in the double-lesioned group (P < 0.05). This behaviour was not different from the one observed after chronic levodopa treatment. These results suggest that levodopa-induced dyskinesias in the 6-OHDA-lesioned rats were not affected by the additional noradrenergic lesion, whereas this last condition was sufficient to worse the cognitive performance deficit produced by the dopaminergic lesion. © 2009 Springer-Verlag., This work was supported by a grant from the Ministerio de Sanidad y Consumo (FIS 05/0094), from the Ministerio de Sanidad y Consumo (FIS 405/707) and from the Fundacion Mª Francisca de Roviralta. Esther Aguilar was partially financed by the programme: Ayudas para Contratos de Apoyo a la Investigación en el Sistema Nacional de Salud from the Ministerio de Sanidad y Consumo of Spanish Government.

A decrease in noradrenergic activity in Parkinson's disease might play a critical role in long-term motor complications associated with chronic dopaminergic replacement. Using the rat model of parkinsonism with an additional noradrenergic degeneration induced by the N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) toxin we evaluated whether the circling motor activity and dose-failure episodes induced by levodopa (L-DOPA) differ between single (6-OHDA) and double (6-OHDA + DSP-4) denervated animals challenged with a single daily dose of L-DOPA. While single-lesioned animals showed a sensitization-desensitization turning response with a significant increase on day 15 and a decrease on day 22, in double-lesioned animals, the turning activity was maximal from day 1 and did not decay on day 22. Double-lesioned rats exhibited significantly higher number of turns on days 15 and 22 and a significantly lower percentage of dose-failure episodes during treatment. Noradrenergic denervation appears to be associated with prolonged long-term dopaminergic sensitization. This type of response appears to be comparable to that in the clinical setting with intermittent L-DOPA administration where no desensitization occurs once the abnormal response is established.

Besides dopaminergic deficiency, other neurotransmitter systems such as noradrenergic nuclei are affected in Parkinson's disease. Locus coeruleus degeneration might influence the response to dopamine replacement and the presence of long-term complications such as dyskinesias. In this scenario of noradrenergic and dopaminergic neurodegeneration, behavioural effects induced by dopaminergic-interacting drugs are incompletely known. We investigated whether noradrenergic lesion modulates the levodopa (l-DOPA) response and modifies the response to adenosine antagonists and its interaction with l-DOPA. We examined the motor behaviour induced by: 1) subthreshold doses of l-DOPA (2mg/kg, i.p.), 2) the adenosine-receptor antagonist caffeine (10mg/kg), and 3) the combination of l-DOPA (2mg/kg) and caffeine (10mg/kg). Each study was done in two experimental conditions: a) rats with unilateral 6-OHDA lesion and b) rats with a lesion of the nigrostriatal pathway (6-OHDA) combined with selective denervation of locus coeruleus-noradrenergic terminal fields by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). While only 28% of the 6-OHDA-lesioned animals presented circling behaviour after l-DOPA challenge, all (100%) double-denervated animals rotated after the same l-DOPA dose (p0.05). No statistical differences in the percentage of rotating animals were observed between single- and double-denervated rats after caffeine challenge. Combined l-DOPA-caffeine challenge produced rotational behaviour in all (100%) single- and double-denervated rats. No differences in total turns were observed between single- and double-denervated animals in each treatment condition. These findings suggest that additional noradrenergic denervation selectively decreases the motor threshold to l-DOPA treatment without modifying the magnitude or the pattern of the motor response to adenosinergic antagonism.

The purpose of the present study was to study the neuroanatomical alterations in patients with bipolar disorder by structural brain assessment with neuroimaging techniques. Method: We studied 241 adult patients (aged 35−65) who were admitted to an Inpatient Unit between 1st of January of 2011 and 31st of December of 2012 with a diagnosis of bipolar disorder. We made an observational study about neuroanatomical changes, correlating macrostructural alterations assessed by neuroimaging techniques (magnetic resonance imaging), average stay and age. Results: From a sample of 241 inpatients magnetic resonance imaging was done to 38%. Neuroanatomic abnormalities were not observed in 71.7% of cases (66patients), but they appeared in 28.2% (26 patients). The most frequent alterations observed were: decreased prefrontal area volume (69.23%), decreased temporal area volume (50.0%), lateral ventriculomegaly (38.46%), decreased cerebellar volume (25%), decreased corpus callosum (23.7%) and increased basal ganglia (19.2%). Comparative analysis showed no significant differences in relation to the average stay, 17.65 days in the bipolar patients group without neuroanatomical alteration and 18.77 days in the bipolar patients group with alterations. There were significant differences between neuroanatomical alterations and age (c2 = 5480 (p< 0.05). The mean age of the bipolar patients group with neuroanatomical abnormalities is 60.29 years, and in the unaltered bipolar patients group is 43.45 years. The other sociodemographic variables (gender, source sector: urban or rural) show no significant differences between the group of bipolar patients with neuroanatomical abnormalities and the group of bipolar patients without abnormalities. Conclusions: Structural magnetic resonance imaging study shows that brain abnormalities in bipolar disorders are mostly regional, as supported by previously published studies. These neurostructural abnormalities do not involve longer hospitalizations, but they are correlated with older age. These results support the evolution of the disease but involutional changes due to early ‘aging’ of the brain can not be dismissed

Oxidative stress may play a role in the pathogenesis of Parkinson's disease. We have standardised a new model of dopaminergic-cell toxicity that uses dopamine, which is able to generate free radicals, as a toxin. The effect of this catecholamine on cell viability (MTT staining) was dose-dependent, reaching 65% of cell loss at a dopamine concentration of 300 μm. In this model, the protective effect of a novel MAO-B inhibitor, N-(2-propynyl)-2-(5-benzyloxy-indolyl) methylamine (PF 9601N), was studied and compared with the effect of l-deprenyl assayed under the same experimental conditions. Whereas PF 9601N (50 μm and 100 μm) showed a significant protective effect, this was not the case with l-deprenyl. This different behaviour could be explained in terms of difference in antioxidant capacity. The toxicity induced in PC12 cells by 300 μm dopamine was partially reversed by incubating it in the presence of GBR-12909, a dopamine-transporter blocker. The results indicated that, besides the intracellular toxicity effect of dopamine, another non-specific extracellular mechanism could be involved.

M. Serra-Blasco1 °, J. De Diego-Adelino1, D. Puigdemont1, Y. Vives-Gilabert2, A. Santos3, I. Crespo3, A. Martin-Blanco1, E. Alvarez1, V. Perez1, M.J. Portella1 1Institut d’Investigacio Biomedica Sant Pau (IIB Sant Pau) Universitat Autonoma de Barceona (UAB) Centro de Investigacion Biomedica en Red de Salud Mental (CIBERSAM), Department of Psychiatry, Barcelona, Spain; 2INNDACYT, Department of Medical Imaging, Barcelona, Spain; 3Hospital de la Santa Creu i Sant Pau Universitat Autonoma de Barcelona (UAB) Institut d’Investigacio Biomedica Sant Pau (IIB Sant Pau) Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Department of Endocrinology, Barcelona, Spa

Three different indolalkylamine derivatives (FA 102, FA 69, FA 70) having in common an -OH group at 5 position of the indole ring and differing in the presence of a methyl group at the N or the acetylenic group of the side chain, have been synthesized and assayed as monoamine oxidaseA (MAO-A) [E.C.1.4.3.4] inhibitors. They were effective inhibitors with, in some cases, similar potencies to clorgyline. “In vitro” experiments were performed on rat brain synaptosomes to investigate whether these MAO-A inhibitors had any effect on noradrenaline (NA), dopamine (DA) and 5hydroxytryptamine (5-HT) transport systems in different rat brain regions. The effect of these drugs were compared with those of clorgyline and 1deprenyl. FA 102, FA 69, FA 70 behaved as inhibitors of 3H-monoamine uptake with similar rank of order of potency for amine uptake inhibition: 5-HT > DA > NA. The IC50 values for FA 102, FA 69, FA 70, respectively, were: 17 μM, 60 μM, 18 μM for 5HT uptake in cortex and 37 μM, 55 μM and 20 μM in hippocampus; 70 μM, 385 μM, 695 μM for NA uptake in cortex and 315 μM, 255 μM and 600 μM in hypothalamus; 270 μM, 160 μM, 40 μM for DA uptake in striatum. l-Deprenyl was a very poor inhibitor of monoamine uptake, whereas clorgyline behaved similarly to these indolalkylamine derivatives. Comparing these results with the IC50 values of Citalopram, nisoxetine and GBR12909, specific and selective inhibitors of 5-HT, NA and DA transport systems respectively, indicated that these indolalkylamine derivatives interact more strongly with the 5HT uptake system.

A series of N-allenic analogues of tryptamine in which the side chain is located at the 2 position of the indole ring, but which differed in the ring and side-chain nitrogen substituents, were assayed kinetically as MAO A and MAO B inhibitors. All the compounds studied were mechanism-based inhibitors. The kinetic constants of each inhibition step Ki and ki, were determined for both MAO A and B. The data obtained indicated that these allenic derivatives show a greater selectivity and potency towards MAO A as inhibitors than the corresponding acetylenic derivatives.

Different methoxy indolalkylamines based on a common structure, and differing in the side chain attached at the 2 position of the indole ring were studied as MAO A inhibitors. Some are acetylenic derivatives and consequently might behave as “suicide” MAO inhibitors (FA 42, FA 43, FA 45). The rest of compounds are the corresponding parent amines and they might behave as MAO substrates (FA 51, FA 52, FA 53, FA 54).

BackgroundElectroconvulsive therapy (ECT) cannot always be effective for Treatment Resistant Depression. Deep brain stimulation (DBS), a procedure that involves the direct implantation of stimulation electrodes in localized brain regions with the aim of modulating local and connected abnormal activity, has recently been gaining momentum as an alternative treatment modality for the most severe TRD patients. However, there is minimal experience with ECT in patients who have undergone DBS procedures.MethodsWe present two cases of patients who remitted from TRD after SCG-DBS, and some months after they suffered a relapse that was treated with ECT.ResultsBefore DBS intervention, ECT was not capable to sustain response more than two weeks beyond and was even bad tolerated by these patients. DBS was effective for both patients until a severe relapse occurred (after 4 and 14 months, respectively). Optimization of medication did not elicit response, given the seriousness of symptoms and their previous treatment resistance. Therefore, neurostimulator was turned off in order to administer ECT to both patients. After usual series of sessions set at corresponding parameters over 3 weeks, using bitemporal electrode placement, the episode remitted. Deep brain stimulator was turned on again, and they were in remission until the present moment.ConclusionsThe use of ECT proved to be effective without adverse effects to the patients or to the DBS hardware. The modulation of SCG activity and its downstream targets might also serve as a trigger for the therapeutic effect of formerly useful or even never-effective antidepressant strategies.

BackgroundDeep brain stimulation (DBS) of the subcallosal cingulate gyrus (SCG) has been suggested to improve depressive symptoms in treatment-resistant depression (TRD). We now report preliminary results of DBS and one-year follow up in six patients.MethodsSix patients with severe TRD (Thase Resistance Index>4) underwent DBS surgery and subsequent monthly assessments. DBS response was defined as ≥50% reduction in the 17-item Hamilton Depression Rating Scale (HDRS) or HDRS< 8 (remission). Electrodes location was assessed in each patient by means of pre/post-DBS MRIs co-registration.ResultsDBS led to early and late reductions of average HDRS (from 22.5 to 9.8 and 6.25 respectively, see Figure 1 for evolution of HDRS mean scores). One month after surgery 16.7% of patients met criteria for response and for remission. Three months after response rates increased to 66.7% while remission rates were maintained. At six months, 66.7% of patients were responders. After 9 months, response rates arose up to 83.4% and these rates were largely maintained at 12 months. Remission rates showed similar growth over follow-up. No substantial differences were observed in electrodes location, and they were not found to be related to response or remission rates. The number of serious adverse effects was small with no patient experiencing permanent deficits.ConclusionsThis study suggests that DBS is relatively safe and provides significant improvement in patients with TRD. Improvement on average seems to be linearly progressive and, once melioration is achieved, it is maintained for at least one year. The procedure is well tolerated.