Psilocybin with psychological support for treatment-resistant depression: six-month follow-up.

RATIONALE: Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy. OBJECTIVES: Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression. METHODS: Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure. RESULTS: Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen's d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen's d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. CONCLUSIONS: Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

Compound heterozygous PNPLA6 mutations cause Boucher-Neuhäuser syndrome with late-onset ataxia.

PNPLA6 mutations, known to be associated with the development of motor neuron phenotypes, have recently been identified in families with Boucher-Neuhäuser syndrome. Boucher-Neuhäuser is a rare autosomal recessive syndrome characterized by the co-occurrence of cerebellar ataxia, hypogonadotropic hypogonadism, and chorioretinal dystrophy. Gait ataxia in Boucher-Neuhäuser usually manifests before early adulthood, although onset in the third or fourth decade has also been reported. However, given the recent identification of PNPLA6 mutations as the cause of this condition, the determining factors of age of symptom onset still need to be established. Here, we have identified a sporadic Boucher-Neuhäuser case with late-onset gait ataxia and relatively milder retinal changes due to compound heterozygous PNPLA6 mutations. Compound heterozygosity was confirmed by cloning and sequencing the patient's genomic DNA from coding exons 26-29. Furthermore, both mutations (one novel and one known) fell in the phospholipase esterase domain, where most pathogenic mutations seem to cluster. Taken together, we herein confirm PNPLA6 mutations as the leading cause of Boucher-Neuhäuser syndrome and suggest inquiring about a history of hypogonadism or visual changes in patients presenting with late-onset gait ataxia. We also advocate for neuroophthalmologic evaluation in suspected cases.

Copy number variants and therapeutic response to antidepressant medication in major depressive disorder.

It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant.

Genome-wide association analysis of copy number variation in recurrent depressive disorder.

Large, rare copy number variants (CNVs) have been implicated in a variety of psychiatric disorders, but the role of CNVs in recurrent depression is unclear. We performed a genome-wide analysis of large, rare CNVs in 3106 cases of recurrent depression, 459 controls screened for lifetime-absence of psychiatric disorder and 5619 unscreened controls from phase 2 of the Wellcome Trust Case Control Consortium (WTCCC2). We compared the frequency of cases with CNVs against the frequency observed in each control group, analysing CNVs over the whole genome, genic, intergenic, intronic and exonic regions. We found that deletion CNVs were associated with recurrent depression, whereas duplications were not. The effect was significant when comparing cases with WTCCC2 controls (P=7.7 × 10(-6), odds ratio (OR) =1.25 (95% confidence interval (CI) 1.13-1.37)) and to screened controls (P=5.6 × 10(-4), OR=1.52 (95% CI 1.20-1.93). Further analysis showed that CNVs deleting protein coding regions were largely responsible for the association. Within an analysis of regions previously implicated in schizophrenia, we found an overall enrichment of CNVs in our cases when compared with screened controls (P=0.019). We observe an ordered increase of samples with deletion CNVs, with the lowest proportion seen in screened controls, the next highest in unscreened controls and the highest in cases. This may suggest that the absence of deletion CNVs, especially in genes, is associated with resilience to recurrent depression.

Depressive disorder moderates the effect of the FTO gene on body mass index.

There is evidence that obesity-related disorders are increased among people with depression. Variation in the FTO (fat mass and obesity associated) gene has been shown to contribute to common forms of human obesity. This study aimed to investigate the genetic influence of polymorphisms in FTO in relation to body mass index (BMI) in two independent samples of major depressive disorder (MDD) cases and controls. We analysed 88 polymorphisms in the FTO gene in a clinically ascertained sample of 2442 MDD cases and 809 controls (Radiant Study). In all, 8 of the top 10 single-nucleotide polymorphisms (SNPs) showing the strongest associations with BMI were followed-up in a population-based cohort (PsyCoLaus Study) consisting of 1292 depression cases and 1690 controls. Linear regression analyses of the FTO variants and BMI yielded 10 SNPs significantly associated with increased BMI in the depressive group but not the control group in the Radiant sample. The same pattern was found in the PsyCoLaus sample. We found a significant interaction between genotype and affected status in relation to BMI for seven SNPs in Radiant (P<0.0057), with PsyCoLaus giving supportive evidence for five SNPs (P-values between 0.03 and 0.06), which increased in significance when the data were combined in a meta-analysis. This is the first study investigating FTO and BMI within the context of MDD, and the results indicate that having a history of depression moderates the effect of FTO on BMI. This finding suggests that FTO is involved in the mechanism underlying the association between mood disorders and obesity.

Evaluation of optic neuropathy in multiple sclerosis using low-contrast visual evoked potentials.

BACKGROUND: Contrast acuity (identification of low-contrast letters on a white background) is frequently reduced in patients with demyelinating optic neuropathy associated with multiple sclerosis (MS), even when high-contrast (Snellen) visual acuity is normal. Since visual evoked potentials (VEPs) induced with high-contrast pattern-reversal stimuli are typically increased in latency in demyelinating optic neuropathy, we asked if VEPs induced with low-contrast stimuli would be more prolonged and thus helpful in identifying demyelinating optic neuropathy in MS. METHODS: We studied 15 patients with clinically definite MS and 15 age-matched normal controls. All subjects underwent a neuro-ophthalmologic assessment, including measurement of high-contrast visual acuity and low-contrast acuities with 25%, 10%, 5%, 2.5%, and 1.25% contrast Sloan charts. In patients with MS, peripapillary retinal nerve fiber layer (RNFL) thickness was determined using optical coherence tomography. Monocular VEPs were induced using pattern-reversal checkerboard stimuli with 100% and 10% contrast between checks, at 5 spatial frequencies (8-130 minutes of arc). RESULTS: VEP latencies were significantly increased in response to low- compared with high-contrast stimuli in both groups. VEP latencies were significantly greater in patients with MS than controls for both high- and low-contrast stimuli. VEP latencies correlated with high- and low-contrast visual acuities and RNFL thickness. VEPs were less likely to be induced with low- than with high-contrast stimuli in eyes with severe residual visual loss. CONCLUSIONS: Visual evoked potentials obtained in patients with multiple sclerosis using low-contrast stimuli are increased in latency or absent when compared with those obtained using high-contrast stimuli and, thus, may prove to be helpful in identifying demyelinating optic neuropathy.

Pain in ischaemic ocular motor cranial nerve palsies.

AIM: Pain is a common feature of microvascular ischaemic ocular motor cranial nerve palsies (MP). The natural history of pain in this condition has not been studied. The purpose of this report is to define the spectrum of pain in isolated MP, with special reference to diabetic versus non-diabetic patients. DESIGN AND METHODS: Retrospective and prospective chart review was performed on 87 patients with acute-onset MP of a single cranial nerve (CN III, oculomotor; CN IV, trochlear; CN VI, abducens) that progressively improved or resolved over 6 months. RESULTS: Five of the 87 patients had two events, making the total number events 92. There were 39 (42.4%) CN III palsies, five (5.4%) CN IV palsies and 48 (52.2%) CN VI palsies. Thirty-six (41%) patients had diabetes. Pain was present in 57 (62%) events. The majority of diabetic and non-diabetic patients had pain. Pain preceded diplopia by 5.8 (SD 5.5) days in one-third of events. There was a trend towards greater pain with CN III palsies, but this was not statistically significant. Patients who experienced severe pain tended to have pain for a longer duration (26.4 (SD 21.7) days compared with 10.8 (SD 8.3) and 9.5 (SD 9) days for mild and moderate pain, respectively). There was no correlation between having diabetes and experiencing pain. CONCLUSIONS: The majority of MP are painful, regardless of the presence or absence of diabetes. Pain may occur prior to or concurrent with the onset of diplopia. Non-diabetic and diabetic patients presented with similar pain characteristics, contrary to the belief that diabetic patients have more pain associated with MP.

Neuromuscular junction dysfunction in Miller Fisher syndrome.

The Miller Fisher syndrome (MFS) is a variant of Guillain-Barre syndrome with the clinical triad of areflexia, ataxia, and ophthalmoparesis. The classic pathologic mechanism of disease is considered to be peripheral nerve demyelination. We present a patient with binocular diplopia and a diagnosis of myasthenia gravis from 15 years prior. Electrophysiologic studies revealed a decremental response on repetitive nerve stimulation, suggesting recurrent myasthenia. However, pupillary light-near dissociation and areflexia were present and positive anti-GQ1b antibodies confirmed MFS. This patient highlights a developing recognition of impaired neuromuscular transmission in MFS. His presentation is discussed in the context of the animal and human literature on neuromuscular junction abnormalities in MFS.

Linezolid-associated toxic optic neuropathy.

The oxazolidinone antimicrobial linezolid is effective against gram-positive bacteria. Although maximal recommended therapy is 28 days, treatment durations greater than this are common. Linezolid may cause reversible optic neuropathy and irreversible peripheral neuropathy after months of treatment. Three cases of linezolid-induced optic and peripheral neuropathy are described, and previously reported cases of linezolid-induced optic neuropathy are reviewed. The mechanism of neural toxicity may be impairment of mitochondrial protein synthesis.

Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS).

BACKGROUND: Late-onset Tay-Sachs disease (LOTS) is an adult-onset, autosomal recessive, progressive variant of GM2 gangliosidosis, characterized by involvement of the cerebellum and anterior horn cells. OBJECTIVE: To determine the range of visual and ocular motor abnormalities in LOTS, as a prelude to evaluating the effectiveness of novel therapies. METHODS: Fourteen patients with biochemically confirmed LOTS (8 men; age range 24 to 53 years; disease duration 5 to 30 years) and 10 age-matched control subjects were studied. Snellen visual acuity, contrast sensitivity, color vision, stereopsis, and visual fields were measured, and optic fundi were photographed. Horizontal and vertical eye movements (search coil) were recorded, and saccades, pursuit, vestibulo-ocular reflex (VOR), vergence, and optokinetic (OK) responses were measured. RESULTS: All patients showed normal visual functions and optic fundi. The main eye movement abnormality concerned saccades, which were "multistep," consisting of a series of small saccades and larger movements that showed transient decelerations. Larger saccades ended earlier and more abruptly (greater peak deceleration) in LOTS patients than in control subjects; these changes can be attributed to premature termination of the saccadic pulse. Smooth-pursuit and slow-phase OK gains were reduced, but VOR, vergence, and gaze holding were normal. CONCLUSIONS: Patients with late-onset Tay-Sachs disease (LOTS) show characteristic abnormalities of saccades but normal afferent visual systems. Hypometria, transient decelerations, and premature termination of saccades suggest disruption of a "latch circuit" that normally inhibits pontine omnipause neurons, permitting burst neurons to discharge until the eye movement is completed. These measurable abnormalities of saccades provide a means to evaluate the effects of novel treatments for LOTS.

Diffuse dural enhancement in cavernous sinus dural arteriovenous fistula.

We describe unusually extensive contrast enhancement of the dura mater on MRI in a case of dural arteriovenous fistula of the cavernous sinus.

Electrolytic oxygen generation for subsurface delivery: effects of precipitation at the cathode and an assessment of side reactions.

This research investigated the oxygen-generating characteristics and side reactions of an electrolytic cell assembly that could be used to remediate sites with contaminants that are amenable to aerobic biodegradation. The oxygen-generating capabilities of new electrolytic cells and cells with light and heavy calcium carbonate precipitates on the cathode were evaluated in the laboratory under current densities ranging from 0.5 to 5.0 mA/cm2. Higher current densities resulted in higher mass transfer coefficients (K(L)a) and greater saturation oxygen concentrations (Csat). As the cathodic deposits increased, the K(L)a tended to decrease and the Csat tended to increase. The oxygen transfer efficiency (OTE) did not vary as a function of current density or cathode coating, while the average OTE for all the tests was 67%. Laboratory column tests showed that chlorine production increased with current density and depended on chloride levels in the water. Hydrogen peroxide was generated at low concentrations (< 1 mg/L) and at higher levels when chloride was absent in the feed solution. Calcium removal from solution increased with current density and resulted in a decrease in solution pH. Tests at a field monitoring well showed average Csat levels of 16.9 mg/L after 14 days of operation, no chlorine production because of low chloride levels in the well, artificially elevated hydrogen peroxide levels because of background interferences, and a pH decrease of 2.4 units. With passive venting, the average hydrogen gas levels at the headspace of the well were less than 1%.

Tracheal constrictor drive above the apneic threshold in anesthetized dogs.

We have previously shown that raising arterial PCO(2) (Pa(CO(2))) by small increments in dogs ventilated below the apneic threshold (AT) results in almost complete tracheal constriction before the return of phrenic activity (Dickstein JA, Greenberg A, Kruger J, Robicsek A, Silverman J, Sommer L, Sommer D, Volgyesi G, Iscoe S, and Fisher JA. J Appl Physiol 81: 1844-1849, 1996). We hypothesized that, if increasing chemical drive above the AT mediates increasing constrictor drive to tracheal smooth muscle, then pulmonary slowly adapting receptor input should elicit more tracheal dilation below the AT than above. In six methohexital sodium-anesthetized, paralyzed, and ventilated dogs, we measured changes in tracheal diameter in response to step increases in tidal volume (VT) or respiratory frequency (f) below and above the AT at constant Pa(CO(2)) ( approximately 40 and 67 Torr, respectively). Increases in VT (400-1,200 ml) caused significantly more (P = 0.005) tracheal dilation below than above AT (7.0 +/- 2.2 vs. 2.8 +/- 1.0 mm, respectively). In contrast, increases in f (14-22 breaths/min) caused similar (P = 0.93) tracheal dilations below and above (1.0 +/- 1.3 and 1.0 +/- 0.8 mm, respectively) AT. The greater effectiveness of dilator stimuli below compared with above the AT is consistent with the hypothesis that drive to tracheal smooth muscle increases even after attainment of maximal constriction. Our results emphasize the importance of controlling PCO(2) with respect to the AT when tracheal smooth muscle tone is experimentally altered.

A biosensor assay for studying ligand-membrane receptor interactions: binding of antibodies and HIV-1 Env to chemokine receptors.

The HIV envelope (Env) protein mediates entry into cells by binding CD4 and an appropriate coreceptor, which triggers structural changes in Env that lead to fusion between the viral and cellular membranes. The major HIV-1 coreceptors are the seven transmembrane domain chemokine receptors CCR5 and CXCR4. The type of coreceptor used by a virus strain is an important determinant of viral tropism and pathogenesis, and virus-receptor interactions can be therapeutic targets. However, Envs from many virus strains interact with CXCR4 and CCR5 with low affinity such that direct study of this important interaction is difficult if not impossible using standard cell-surface binding techniques. We have developed an approach that makes it possible to study ligand binding to membrane proteins, including Env-coreceptor interactions, using an optical biosensor. CCR5, CXCR4, and other membrane proteins were incorporated into retrovirus particles, which were purified and attached to the biosensor surface. Binding of conformationally sensitive antibodies as well as Env to these receptors was readily detected. The equilibrium dissociation constant for the interaction between an Env derived from the prototype HIV-1 strain IIIB for CXCR4 was approximately 500 nM, explaining the difficulty in measuring this interaction using standard equilibrium binding techniques. Retroviral pseudotypes represent easily produced, stable, homogenous structures that can be used to present a wide array of single and multiple membrane-spanning proteins in a native lipid environment for biosensor studies, thus avoiding the need for detergent solubilization, purification, and reconstitution. The approach should have general applicability and can be used to correlate Env-receptor binding constants to viral tropism and pathogenesis.

A simple "new" method to accelerate clearance of carbon monoxide.

The currently recommended prehospital treatment for carbon monoxide (CO) poisoning is administration of 100% O(2). We have shown in dogs that normocapnic hyperpnea with O(2) further accelerates CO elimination. The purpose of this study was to examine the relation between minute ventilation (V E) and the rate of elimination of CO in humans. Seven healthy male volunteers were exposed to CO (400 to 1,000 ppm) in air until their carboxyhemoglobin (COHb) levels reached 10 to 12%. They then breathed either 100% O(2) at resting V E (4.3 to 9.0 L min) for 60 min or O(2) containing 4.5 to 4.8% CO(2) (to maintain normocapnia) at two to six times resting V E for 90 min. The half-time of the decrease in COHb fell from 78 +/- 24 min (mean +/- SD) during resting V E with 100% O(2) to 31 +/- 6 min (p < 0. 001) during normocapnic hyperpnea with O(2). The relation between V E and the half-time of COHb reduction approximated a rectangular hyperbola. Because both the method and circuit are simple, this approach may enhance the first-aid treatment of CO poisoning.

Multiple charged and aromatic residues in CCR5 amino-terminal domain are involved in high affinity binding of both chemokines and HIV-1 Env protein.

CCR5 is a functional receptor for MIP-1alpha, MIP-1beta, RANTES (regulated on activation normal T cell expressed), MCP-2, and MCP-4 and constitutes the main coreceptor for macrophage tropic human and simian immunodeficiency viruses. By using CCR5-CCR2b chimeras, we have shown previously that the second extracellular loop of CCR5 is the major determinant for chemokine binding specificity, whereas the amino-terminal domain plays a major role for human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus coreceptor function. In the present work, by using a panel of truncation and alanine-scanning mutants, we investigated the role of specific residues in the CCR5 amino-terminal domain for chemokine binding, functional response to chemokines, HIV-1 gp120 binding, and coreceptor function. Truncation of the amino-terminal domain resulted in a progressive decrease of the binding affinity for chemokines, which correlated with a similar drop in functional responsiveness. Mutants lacking residues 2-13 exhibited fairly weak responses to high concentrations (500 nM) of RANTES or MIP-1beta. Truncated mutants also exhibited a reduction in the binding affinity for R5 Env proteins and coreceptor activity. Deletion of 4 or 12 residues resulted in a 50 or 80% decrease in coreceptor function, respectively. Alanine-scanning mutagenesis identified several charged and aromatic residues (Asp-2, Tyr-3, Tyr-10, Asp-11, and Glu-18) that played an important role in both chemokine and Env high affinity binding. The overlapping binding site of chemokines and gp120 on the CCR5 amino terminus, as well as the involvement of these residues in the epitopes of monoclonal antibodies, suggests that these regions are particularly exposed at the receptor surface.

Effect of nonpolar substitutions of the conserved Phe11 in the fusion peptide of HIV-1 gp41 on its function, structure, and organization in membranes.

The fusion domain of the HIV-1 envelope glycoprotein (gp120-gp41) is a conserved hydrophobic region located at the N-terminus of the transmembrane subunit (gp41). A prominent feature of this domain is a conserved five-residue "FLGFL" sequence at positions 8-12. Mutation of the highly conserved Phe(11) to Val (F11V), presumed not to significantly affect the hydrophobicity and the structure of this region, has been shown to decrease the level of syncytium formation and virus infectivity. Here we show that the substitution of Gly for Phe(11) (F11G) reduces cell-cell fusion activity by 80-90%. To determine the effect of these mutations on the properties of the fusion peptide, a 33-residue peptide (WT) identical to the extended fusion domain and its F11V and F11G mutants were synthesized, fluorescently labeled, and studied with respect to their function, structure, and organization in phospholipid membranes. The WT peptide alone induced fusion of both zwitterionic (PC/Chol) and negatively charged (PS/PC/Chol and POPG) vesicles, in contrast to a 23-mer fusion peptide lacking the C-terminal domain which has been shown to be inactive with PC vesicles but able to induce fusion of POPG vesicles which had been preaggragated with Ca(2+) or Mg(2+). The F11V peptide preserved 50% activity, and the F11G peptide was virtually inactive. ATR-FTIR spectroscopy indicated similar secondary structure of the peptides in multibilayers that was independent of membrane composition. Furthermore, all the peptides increased the extent of lipid disorder to a similar extent, but the kinetics of amide II H to D exchange was in the following order: F11G > F11V > WT. Fluorescence studies in the presence of membranes, as well as SDS-PAGE, revealed that the WT and F11V peptides self-associate to similar levels while F11G exhibited a decreased level of self-association. The data suggest that the FLGFL motif contributes to the functional organization of the HIV-1 fusion peptide and that the C-terminal domain following the fusion peptide contributes to the membrane fusion process.

Isocapnic hyperpnea accelerates carbon monoxide elimination.

A major impediment to the use of hyperpnea in the treatment of CO poisoning is the development of hypocapnia or discomfort of CO2 inhalation. We examined the effect of nonrebreathing isocapnic hyperpnea on the rate of decrease of carboxyhemoglobin levels (COHb) in five pentobarbital-anesthetized ventilated dogs first exposed to CO and then ventilated with room air at normocapnia (control). They were then ventilated with 100% O2 at control ventilation, and at six times control ventilation without hypocapnia ("isocapnic hyperpnea") for at least 42 min at each ventilator setting. We measured blood gases and COHb. At control ventilation, the half-time for elimination of COHb (t1/2) was 212 +/- 17 min (mean +/- SD) on room air and 42 +/- 3 min on 100% O2. The t1/2 decreased to 18 +/- 2 min (p < 0.0005) during isocapnic hyperpnea. In two similarly prepared dogs treated with hyperbaric O2, the t1/2 were 20 and 28 min. We conclude that isocapnic hyperpnea more than doubles the rate of COHb elimination induced by normal ventilation with 100% O2. Isocapnic hyperpnea could improve the efficacy of the standard treatment of CO poisoning, 100% O2 at atmospheric or increased pressures.