Jeffrey M. Schwartz

FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder

In subjects with obsessive-compulsive disorder (OCD), lower pre-treatment metabolism in the right orbitofrontal cortex (OFC) and anterior cingulate gyrus (AC) has been associated with a better response to clomipramine. We sought to determine pre-treatment metabolic predictors of response to behavioral therapy (BT) vs. pharmacotherapy in subjects with OCD. To do this, [18F]fluorodeoxyglucose positron emission tomography scans of the brain were obtained in subjects with OCD before treatment with either BT or fluoxetine. A Step-Wise Variable Selection was applied to normalized pre-treatment glucose metabolic rates in the OFC, AC, and caudate by treatment response (change in Yale-Brown Obsessive-Compulsive Scale) in the larger BT group. Left OFC metabolism (normalized to the ipsilateral hemisphere) alone was selected as predicting treatment response in the BT-treated group (F = 6.07, d.f. = 1,17, P = 0.025). Correlations between normalized left OFC metabolism and treatment response revealed that higher normalized metabolism in this region was associated with greater improvement in the BT-treated group (tau = 0.35, P = 0.04), but worse outcome (tau = -0.57, P = 0.03) in the fluoxetine-treated group. These results suggest that subjects with differing patterns of metabolism preferentially respond to BT vs. medication.

Quantum physics in neuroscience and psychology: a neurophysical model of mind–brain interaction

Neuropsychological research on the neural basis of behaviour generally posits that brain mechanisms will ultimately suffice to explain all psychologically described phenomena. This assumption stems from the idea that the brain is made up entirely of material particles and fields, and that all causal mechanisms relevant to neuroscience can therefore be formulated solely in terms of properties of these elements. Thus, terms having intrinsic mentalistic and/or experiential content (e.g. ‘feeling’, ‘knowing’ and ‘effort’) are not included as primary causal factors. This theoretical restriction is motivated primarily by ideas about the natural world that have been known to be fundamentally incorrect for more than three-quarters of a century. Contemporary basic physical theory differs profoundly from classic physics on the important matter of how the consciousness of human agents enters into the structure of empirical phenomena. The new principles contradict the older idea that local mechanical processes alone can account for the structure of all observed empirical data. Contemporary physical theory brings directly and irreducibly into the overall causal structure certain psychologically described choices made by human agents about how they will act. This key development in basic physical theory is applicable to neuroscience, and it provides neuroscientists and psychologists with an alternative conceptual framework for describing neural processes. Indeed, owing to certain structural features of ion channels critical to synaptic function, contemporary physical theory must in principle be used when analysing human brain dynamics. The new framework, unlike its classic-physics-based predecessor, is erected directly upon, and is compatible with, the prevailing principles of physics. It is able to represent more adequately than classic concepts the neuroplastic mechanisms relevant to the growing number of empirical studies of the capacity of directed attention and mental effort to systematically alter brain function.

Rapid effects of brief intensive cognitive-behavioral therapy on brain glucose metabolism in obsessive-compulsive disorder

Brief intensive cognitive-behavioral therapy (CBT) using exposure and response prevention significantly improves obsessive-compulsive disorder (OCD) symptoms in as little as 4 weeks. However, it has been thought that much longer treatment was needed to produce the changes in brain function seen in neuroimaging studies of OCD. We sought to elucidate the brain mediation of response to brief intensive CBT for OCD and determine whether this treatment could induce functional brain changes previously seen after longer trials of pharmacotherapy or standard CBT. [18F]-fluorodeoxyglucose positron emission tomography brain scans were obtained on 10 OCD patients before and after 4 weeks of intensive individual CBT. Twelve normal controls were scanned twice, several weeks apart, without treatment. Regional glucose metabolic changes were compared between groups. OCD symptoms, depression, anxiety and overall functioning improved robustly with treatment. Significant changes in normalized regional glucose metabolism were seen after brief intensive CBT (P=0.04). Compared to controls, OCD patients showed significant bilateral decreases in normalized thalamic metabolism with intensive CBT but had a significant increase in right dorsal anterior cingulate cortex activity that correlated strongly with the degree of improvement in OCD symptoms (P=0.02). The rapid response of OCD to intensive CBT is mediated by a distinct pattern of changes in regional brain function. Reduction of thalamic activity may be a final common pathway for improvement in OCD, but response to intensive CBT may require activation of dorsal anterior cingulate cortex, a region involved in reappraisal and suppression of negative emotions.

Dorsal noradrenergic bundle lesions fail to alter opiate withdrawal or suppression of opiate withdrawal by clonidine.

Previous work has shown that clonidine effectively suppresses many of the signs of opiate withdrawal. The present study was designed to test the hypothesis that the suppression of opiate withdrawal by clonidine is mediated by forebrain noradrenergic projections of the locus coeruleus. Two groups of 24 rats each were subjected to either a 6-hydroxydopamine lesion of the dorsal noradrenergic bundle (Lesion group) or a sham, vehicle injection (Sham group). All rats were made dependent on morphine by subcutaneous implantation of one 75 mg silastic morphine pellet for three days followed by 3 more days with two additional 75 mg pellets. Following removal of the morphine pellet, withdrawal was precipitated in all rats by subcutaneous injection of 4 mg/kg of naloxone. Pretreatment 10 min. before withdrawal with clonidine (0.1 or 0.2 mg/kg) produced a significant attenuation of withdrawal signs as compared to saline injected rats; this effect was equally significant in both sham and lesion groups. Lesions of the locus coeruleus had no effect on withdrawal, nor did they affect the ameliorating action of clonidine. These results substantiate the observation that clonidine can effectively attenuate signs of opiate withdrawal in the rat, but fail to support the hypothesis that these effects are mediated by the forebrain projections of the locus coeruleus.

Prolongation of the antidepressant response to partial sleep deprivation by lithium

Depressed patients given a loading dose of lithium on the first of 2 successive days of partial sleep deprivation (PSD), and kept at maintenance levels thereafter, showed significantly greater prolongation of the antidepressant effects of PSD than patients treated with PSD and placebo, even though the acute elevation in mood derived from PSD was as great on placebo as on lithium. Depression was assessed 3 days after PSD with an augmented version of the Hamilton Rating Scale for Depression. Patients on lithium alone, without PSD, did not have the acute elevation in mood seen in the two PSD groups and had significantly less improvement in depression than those who received PSD with lithium.

Effects of partial sleep deprivation on the diurnal variation of mood and motor activity in major depression

Partial sleep deprivation (PSD), keeping a subject awake from 2 AM to 9 PM produces an acute mood improvement in 60% of patients with major depression. We sought to characterize the timing, subcomponent mood, and motor activity changes of this response. Thirty-seven subjects with major depression were rated with the 6-item Hamilton Depression Scale (HAM-6) at 1 PM and completed the Profile of Mood States (POMS) every 2 hr on the day before and day of PSD. Locomotor activity was monitored continuously during the trial with an automated device. Bipolar I patients responded more frequently than other groups. Positive mood responders had greater improvement than nonresponders in POMS subscales of depression, tension, confusion, and anger. The mood improvement increased steadily during the day, peaked in late afternoon, and declined thereafter. Responders showed significantly higher levels of locomotor activity on the baseline pre-PSD day than did nonresponders. All subjects increased motor activity following sleep deprivation, however.

Lithium sustains the acute antidepressant effects of sleep deprivation: Preliminary findings from a controlled study

Early morning sleep deprivation (patient awake from 0200 to 2200 hours) produces a same-day antidepressant effect in approximately one-half of patients with major depression. Unfortunately, these antidepressant effects are short-lived and patients usually relapse to baseline depression levels within 48 hours. Recent work suggests, however, that the use of lithium with early morning sleep deprivation sustains this rapid antidepressant effect and makes it clinically useful. In a 30-day study, we compared the abilities of four different treatments (lithium plus early morning sleep deprivation, lithium plus a control sleep deprivation procedure, and desipramine with either of the two sleep manipulations) to induce a rapid (next-day) and sustained antidepressant response in 16 depressed patients. Lithium plus early morning sleep deprivation produced a quicker response than lithium with the control sleep deprivation, and the response was sustained for at least 30 days. In this design, however, lithium/early morning sleep deprivation was no faster than either of the two desipramine/sleep deprivation conditions in inducing remission. These results support the results of previous studies and suggest further investigation of this novel sleep/pharmacologic intervention is warranted.

Changes in glucose metabolism in dementia of the Alzheimer type compared with depression: A preliminary report

We evaluated positron emission tomography (PET) in the differential diagnosis of depression and Alzheimers disease. The local cerebral metabolic rate for glucose (LCMRGlc) in the parahippocampal gyrus-hippocampus and the dorsolateral prefrontal cortex were determined. The ratio of the LCMRGlc in those two regions was examined in patients with unipolar depression, bipolar depression, and Alzheimers dementia. An analysis of variance revealed significant overall intergroup differences in values for both hemispheres. Students t test showed significant differences in LCMRGlc for both unipolar and bipolar depression as compared with Alzheimers dementia. These data indicate that PET may be useful in the differential diagnosis of dementia vs. depression.

Trazodone Treatment Response in Obsessive-Compulsive Disorder – Correlated with Shifts in Glucose Metabolism in the Caudate Nuclei

Obsessive-compulsive disorder (OCD) is a severe psychiatric illness that is difficult to treat. The effects of trazodone hydrochloride treatment were studied, both with and without the addition of a monoamine oxidase inhibitor, in OCD patients. Changes in symptoms correlated with changes in local cerebral metabolic rates for glucose (LCMRGlc), as measured by positron emission tomography and the 18F-fluorodeoxyglucose method. All patients whose OCD responded favorably to drug treatment showed a relative increase in glucose metabolism in the heads of the caudate nuclei compared with the metabolic rate in the ipsilateral hemisphere as a whole (ratio LCMRGlc caudate/LCMRGlc hemisphere). Patients who did not respond to treatment did not show an increase in this ratio, and the difference between responders and nonresponders was significant (p less than 0.03). Changes in the ratio LCMRGlc caudate/LCMRGlc hemisphere correlated with changes on OCD and depression rating scales.

Managing co-occurring substance use and pain disorders.

The safest pain treatment strategy for an individual at risk or recovering from addiction is a nonopioid and benzodiazepine-free approach. If an opioid treatment is necessary, the extent of the risk can be stratified by the use of a biopsychosocial assessment and opioid screening tools. Individuals at high risk should have the greatest amount of structure and monitoring. A written informed consent and treatment agreement can provide a framework for the patient and the patient’s family, as well as the clinician. The structure of treatment should specify only that one prescribing physician will write a limited supply of opioids, without refills, until the analgesic efficacy, adverse events, and goals for functional restoration can be assessed. An additional recommendation is that prescriptions should be filled at the same pharmacy with no refill by phone or opportunity for replacement because of loss, damage, or stolen medications. Additionally, random urine drug screens and PDMP reports obtained will help determine if the patient is taking other substances, as well as monitor the patient’s medication use patterns. It is important to assess for risk factors in treating chronic pain with opioids; clinicians need to have a realistic appreciation of the resources available to them and the types of patients that can be managed in their practice. Chronic pain treatment with opioids should not be undertaken in patients who are currently addicted to illicit substances or alcohol. With the support of family and friends, ideally the patient can be motivated to participate in an intensive substance abuse treatment. In patients without an immediate risk, precautionary steps should be taken when prescribing opioids. Clinicians and patients need to review the risk factors for opioid-related problems including younger age, benzodiazepine use, and comorbid conditions such as depression, anxiety, and heavy smoking. Both the provider and the patient need a personal investment in the treatment plan and protocol to increase the safety of opioid treatment. New medications and treatment monitoring are being developed to provide maximal relief for the patient while protecting the public health. The optimal ingredients for safe opioid treatment include a strong provider-patient relationship and clinician training in the assessment and treatment of addiction and pain.