Multiple-therapy-resistant major depressive disorder: a clinically important concept.

Many novel therapeutic options for depression exist that are either not mentioned in clinical guidelines or recommended only for use in highly specialist services. The challenge faced by clinicians is when it might be appropriate to consider such 'non-standard' interventions. This analysis proposes a framework to aid this decision.Declaration of interestIn the past 3 years R.H.M.W. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending advisory boards) from various pharmaceutical companies including Astra Zeneca, Cyberonics, Eli Lilly, Janssen, LivaNova, Lundbeck, MyTomorrows, Otsuka, Pfizer, Roche, Servier, SPIMACO and Sunovion. D.M.B.C. has received fees from LivaNova for attending an advisory board. In the past 3 years A.J.C. has received fees for lecturing from Astra Zeneca and Lundbeck; fees for consulting from LivaNova, Janssen and Allergan; and research grant support from Lundbeck.In the past 3 years A.C. has received fees for lecturing from pharmaceutical companies namely Lundbeck and Sunovion. In the past 3 years A.L.M. has received support for attending seminars and fees for consultancy work (including advisory board) from Medtronic Inc and LivaNova. R.M. holds joint research grants with a number of digital companies that investigate devices for depression including Alpha-stim, Big White Wall, P1vital, Intel, Johnson and Johnson and Lundbeck through his mindTech and CLAHRC EM roles. M.S. is an associate at Blueriver Consulting providing intelligence to NHS organisations, pharmaceutical and devices companies. He has received honoraria for presentations and advisory boards with Lundbeck, Eli Lilly, URGO, AstraZeneca, Phillips and Sanofi and holds shares in Johnson and Johnson. In the past 3 years P.R.A.S. has received support for research, expenses to attend conferences and fees for lecturing and consultancy work (including attending an advisory board) from life sciences companies including Corcept Therapeutics, Indivior and LivaNova. In the past 3 years P.S.T. has received consultancy fees as an advisory board member from the following companies: Galen Limited, Sunovion Pharmaceuticals Europe Ltd, myTomorrows and LivaNova. A.H.Y. has undertaken paid lectures and advisory boards for all major pharmaceutical companies with drugs used in affective and related disorders and LivaNova. He has received funding for investigator initiated studies from AstraZeneca, Eli Lilly, Lundbeck and Wyeth.

New insights into the role of the GABA(A)-benzodiazepine receptor in psychiatric disorder.

BACKGROUND: In the 40 years since the first benzodiazepine was brought into clinical use there has been a substantial growth in understanding the molecular basis of action of these drugs and the role of their receptors in disease states. AIMS: To present current knowledge about the role of the GABA(A)-benzodiazepine receptor in anxiety disorders, new insights into the molecular biology of the receptor complex and neuroimaging studies suggesting involvement of these receptors in disease states. METHOD: An overview of published literature, including some recent data. RESULTS: The molecular biology of this receptor is detailed. Molecular genetic studies suggesting involvement of the GABA(A)-benzodiazepine receptor in animal behaviour and learning are outlined; possible parallels with human psychopathology are discussed. CONCLUSIONS: Current insights into the role of the GABA(A)-benzodiazepine receptor in the action of benzodiazepines and as a factor in disease states, in both animals and humans, may lead to new, more sophisticated interventions at this receptor complex and potentially significant therapeutic gains.

Changes in regional cerebral blood flow elicited by craving memories in abstinent opiate-dependent subjects.

OBJECTIVE: The brain circuitry of opiate craving was investigated with positron emission tomography (PET) imaging of regional cerebral blood flow (rCBF). METHOD: Twelve abstinent opiate-dependent subjects listened to audiotaped autobiographical scripts of an episode of craving and a neutral episode while undergoing a PET scan with the tracer [(15)O]H(2)O. Statistical parametric mapping was used to analyze the PET images of rCBF changes. RESULTS: Comparison of the drug-related and neutral stimulus conditions revealed activation of rCBF in the left medial prefrontal and left anterior cingulate cortices and deactivation in the occipital cortex in response to the drug-related stimulus. A further statistical parametric mapping analysis with a subjective rating of craving as a covariate showed a positive association of between craving and rCBF in the left orbitofrontal cortex. CONCLUSIONS: The patterns of cerebral activation reflect the different brain regions mediating the salience of opiate-related stimuli and the subjective experience of craving for opiates.

Venlafaxine occupation at the noradrenaline reuptake site: in-vivo determination in healthy volunteers.

Venlafaxine, a serotonin and noradrenaline reuptake inhibitor, is an effective antidepressant at doses of 75 mg p.o. daily and above. Preclinical and healthy volunteer studies have demonstrated that venlafaxine is more potent at the serotonin than at the noradrenaline reuptake site, with noradrenergic blocking effects being observed at doses >75 mg p.o. in man. We used the Multiple Organs Coincidences Counter and [11C] meta hydroxy ephedrine (MHED) to test whether significant occupation of cardiac sympathetic neurones was achieved in man in vivo after the acute administration of venlafaxine 75 mg p.o. in nine healthy volunteers. MHED is a tracer which binds at the noradrenaline reuptake site. This study demonstrates that the [11C]MHED signal is significantly reduced after the administration of venlafaxine 75 mg p.o. thus showing that noradrenaline reuptake blockade is observable at this dose. This effect is predominantly seen in volunteers who received > 1 mg/kg venlafaxine.

Desipramine binding to noradrenaline reuptake sites in cardiac sympathetic neurons in man in vivo.

Noradrenergic reuptake blockade is a recognised mechanism of antidepressant action, but the extent of the blockade necessary for therapeutic effect is not known and plasma levels do not provide a guide to therapy. We report a method to assess noradrenaline reuptake blockade in vivo in man using [11C]meta-hydroxyephedrine and the multiple organs' coincidences counter. Eight healthy volunteers had two scans, one with tracer alone and one after preloading with desipramine 50-75 mg p.o. In all subjects, there was an increased washout rate of the radioligand from the heart following preloading (t=4.38; P<0.003) as well as a decrease of the area under the [11C]meta-hydroxyephedrine time activity curve (t=7. 4; P=0.001). In one subject who had three doses of desipramine, the increase in washout rate was dose-dependent. In conclusion, [11C]meta-hydroxyephedrine in the multiple organs' coincidences counter gives a valid, low radiation method to assess noradrenergic reuptake blockade in the clinic.

The neurobiology of social phobia.

Although Social Phobia has been recognised for centuries in comparison with other anxiety disorders, relatively little work has been done to understand its neural basis. The present review attempts to redress this balance by giving an overview of the current state of knowledge in this disorder. By putting together data from the treatment responses to specific agents, the effects of chemical challenges which have been used in other anxiety disorders and by reviewing data on central and peripheral neurotransmitter and endochrine abnormalities, it is possible to begin to generate some potentially testable theories of aetiology and mechanisms. Finally, we review the potential use of neuroimaging techniques to better detail the brain circuits and possibly neurotransmitters involved in social phobia, showing some of our preliminary work using (15)O water blood flow PET activation studies to determine the brain circuits in which metabolism is changed during the experience of social anxiety.

What do brain imaging studies tell us about anxiety disorders?

In-vivo neuroimaging allows the investigation of brain circuits involved in the experience of anxiety and of receptor changes associated with anxiety disorders. This review focuses on studies by research groups who have compared brain activation maps in different forms of anxiety and on binding studies of the benzodiazepine-GABA(A) receptor. Activation studies have revealed the involvement of many brain areas depending on the condition and the paradigm. However, the orbitofrontal cortex/anterior insula and the anterior cingulate are implicated in all the studies and may represent the nodal point between somatic and cognitive symptoms of any form of anxiety. Most studies of binding at the benzodiazepine-GABA(A) receptor are not interpretable because of substantial methodological problems, however, regional and/or global reductions are the most consistent finding in panic disorder.

Brain mechanisms of social anxiety disorder.

The neurobiology of social anxiety disorder is poorly understood, although preliminary research has suggested several possible biological abnormalities. Challenge studies have demonstrated that subjects with social anxiety disorder have a sensitivity to carbon dioxide, cholecystokinin, and caffeine somewhere between that of panic disorder patients and normal controls. Serotonergic pathways may play a role in social anxiety disorder, as shown by the clinical effectiveness of selective serotonin reuptake inhibitors, plus fenfluramine and m-chlorophenylpiperazine challenge studies. Dopaminergic function and striatal dopamine uptake appear to be reduced in social anxiety disorder. There is also evidence for cardiovascular and adrenergic abnormalities. Recently, positron emission tomography has begun to identify brain regions that appear to be uniquely activated in this condition. These results offer the promise of an understanding of the brain mechanisms of social anxiety disorder, but much further research is needed to fully elucidate the neurobiological cause(s) that exist.

Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder: preliminary results from a quantitative PET study.

BACKGROUND: Positron emission tomography (PET) allows the measurement of benzodiazepine-gamma-aminobutyric acidA (GABA(A)) receptor kinetics. We employed flumazenil radiolabeled with carbon 11, a radioligand that labels the benzodiazepine site on the GABA(A) receptor, and fully quantitative, high-sensitivity PET to test the hypothesis that central benzodiazepine site binding is decreased in medication-free patients with panic disorder. METHODS: We compared 7 patients with panic disorder who had been off medication for at least 6 months and who had never abused alcohol with 8 healthy controls. The resulting parametric voxel-by-voxel maps were analyzed by voxel-based and region of interest-based methods using both parametric and nonparametric statistics. RESULTS: The major finding was that there is a global reduction in benzodiazepine site binding throughout the brain in patients with panic disorder compared with controls. There were sex differences in the 2 samples, but a separate analysis excluding women led to the same conclusions. In addition, the loci with the largest regional decrease in binding (right orbitofrontal cortex and right insula) were areas thought to be essential in the central mediation of anxiety. CONCLUSION: These results must be considered preliminary but are congruous with previous clinical psychopharmacologic evidence of involvement of the benzodiazepine-GABA(A) receptor and demonstrate that decreased flumazenil binding at this site may underlie panic disorder.

The frontal lobes and neurosurgery for psychiatric disorders.

The frontal lobe has been the main target for surgical treatment of mental illness over the last 60 years. Initially the surgery was crude and performed on patients with many different psychiatric disorders. Contemporary surgery utilizes stereotactic lesions which interrupt fronto-thalamic and/or fronto-cingulate fibres. The findings of clinical, neurochemical, neuroimaging, neuropsychological and physiological research in this area are summarized. Current advances in clinical neuroscience methods should be used in patients with these lesions to elucidate the neural substrate of post-operative changes and optimize clinical practice.

Analysis of dynamic radioligand displacement or "activation" studies.

We present a simple way of assessing dynamic or time-dependent changes in displacement during single-subject radioligand positron emission tomography (PET) activation studies. The approach is designed to facilitate dynamic activation studies using selective radioligands. These studies are, in principle, capable of characterising functional neurochemistry by analogy with the study of functional neuroanatomy using rCBF activation studies. The proposed approach combines time-dependent compartmental models of tracer kinetics and the general linear model used in statistical parametric mapping. This provides for a comprehensive, voxel-based and data-led assessment of regionally specific effects. The statistical model proposed in this paper is predicated on a single-compartment model extended to allow for time-dependent changes in kinetics. We have addressed the sensitivity and specificity of the analysis, as it would be used operationally, by applying the analysis to 11C-Flumazenil dynamic displacement studies. The activation used in this demonstration study was a pharmacological (i.v. midazolam) challenge, 30 min after administration of the tracer. We were able to demonstrate, and make statistical inferences about, regional increases in k2 (or decreases in the volume of distribution) in prefrontal and other cortical areas.

Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

Neurosurgery for mental disorders (NMD) A clinical worldwide perspective: past, present and future.

The use of neurosurgery for mental disorders (NMD) is a clinical issue that involves many ethical considerations. It is a treatment that offers hope for many patients with severe and debilitating affective and anxiety disorders and should be widely available. Its current use worldwide (UK, Sweden, US, Australasia, Europe) is reviewed and the types of procedures currently used are explained (stereotactic subcaudate tractotomy, anterior capsulotomy, cingulotomy, limbic leucotomy). In addition, clinical strategies for the evaluation and management of patients both prior to and following NMD are discussed.

Benzodiazepine site pharmacokinetic/pharmacodynamic quantification in man: direct measurement of drug occupancy and effects on the human brain in vivo.

To date, the study of the relationship between drug occupancy and action in the brain has had to rely on the use of either animal models or of indirect kinetic measures in man, e.g. serum concentrations of unbound drug (as a measure of "free" drug in brain). We describe the first set of experiments which directly measure agonist-induced changes in both pharmacodynamic effects and pharmacokinetic parameters simultaneously and which demonstrate the feasibility of these studies in man. Five healthy volunteers each had two PET scans using [11C]flumazenil (a radiolabelled benzodiazepine site antagonist) as part of a study investigating kinetic models and the relationship between occupancy and effect of benzodiazepine site ligands. In both studies the [11C]flumazenil was displaced from the brain by infusion of midazolam administered i.v. 30 min into the scan. In one study a higher dose of midazolam was administered than in the other (range 12.5-50 micrograms/kg). Time-activity curves of the concentration of radioligand were derived in 17 different brain regions using a stereotactic automatic method of region selection. We demonstrated that there are significant differences in an index of occupancy, induced by the two different doses of midazolam, both across brain regions and within subjects. There was a significant correlation between measured occupancy index change and pharmacodynamic effects as measured by the peak change in beta 1 spectral power on EEG. There was no significant correlation between dose administered and EEG changes; plasma concentrations of midazolam were correlated with the occupancy index and with the EEG measures. In addition, we have demonstrated that a non-regional total index of brain occupancy can be obtained by analysing the non-tomographic data obtained with the PET scanner (total radioactivity counts head curve) and that this index shows significant correlations both with the dose administered and with the pharmacodynamic measure. This last finding validates the use of other non-tomographic counting techniques (Malizia et al., 1995a) where an index of displacement can be obtained after the administration of less than 1% of the dose of radiation needed for a PET study. These studies are likely to be useful in human psychopharmacology, in particular in the assessment of tolerance and of putative changes in benzodiazepine sensitivity in anxiety disorders. The same principles can be applied to other ligand studies and will be useful to validate current PK/PD models.

Practical management of treatment-resistant affective disorders.

The Geoffrey Knight National Unit was set up in 1970 exclusively for psychosurgery. In recent years it has become increasingly concerned with the development of medication regimens that might avoid the need for surgery. This has offered a unique pharmacotherapeutic opportunity because all the referrals have severe, persistent and treatment-resistant disorders. The scheme of high-dose and combined medication devised is presented and discussed.

The effects of flumazenil in neuropsychiatric disorders.

Flumazenil is a benzodiazepine receptor antagonist. It is currently used mainly in the anaesthetic and emergency rooms to reverse the effect of exogenous benzodiazepines. Its use in a variety of experimental animal models and in human neuropsychiatric disorders continues to generate a wealth of information on the possible role of the benzodiazepine-GABA(A) receptor complex in their pathogenesis. In addition, labelled with carbon-11, flumazenil has proved to be one of the most successful positron emission tomography ligands stimulating research on the role of the benzodiazepine receptor in these disorders. This review focuses on the current state of play of flumazenil as a therapeutic or investigative agent in neuropsychiatry, citing also the relevant animal models.

Outcome after the psychosurgical operation of stereotactic subcaudate tractotomy, 1979-1991.

The outcome of all psychosurgical operations (stereotactic subcaudate tractotomies) performed at the Geoffrey Knight National Unit for Affective Disorders in London since 1979 is reviewed. Of patients who had suffered severe mood or obsessive-compulsive disorders before surgery, 84 of 249 (34%) were well 1 year after. The effects of gender, psychiatric diagnosis, and age on outcome are assessed. The findings are compared with a 1975 outcome study, and explanations for apparent differences are proposed.