A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.

BACKGROUND: Optimal treatment remains uncertain for patients with cognitive impairment that persists or returns after standard IV antibiotic therapy for Lyme disease. METHODS: Patients had well-documented Lyme disease, with at least 3 weeks of prior IV antibiotics, current positive IgG Western blot, and objective memory impairment. Healthy individuals served as controls for practice effects. Patients were randomly assigned to 10 weeks of double-masked treatment with IV ceftriaxone or IV placebo and then no antibiotic therapy. The primary outcome was neurocognitive performance at week 12-specifically, memory. Durability of benefit was evaluated at week 24. Group differences were estimated according to longitudinal mixed-effects models. RESULTS: After screening 3368 patients and 305 volunteers, 37 patients and 20 healthy individuals enrolled. Enrolled patients had mild to moderate cognitive impairment and marked levels of fatigue, pain, and impaired physical functioning. Across six cognitive domains, a significant treatment-by-time interaction favored the antibiotic-treated group at week 12. The improvement was generalized (not specific to domain) and moderate in magnitude, but it was not sustained to week 24. On secondary outcome, patients with more severe fatigue, pain, and impaired physical functioning who received antibiotics were improved at week 12, and this was sustained to week 24 for pain and physical functioning. Adverse events from either the study medication or the PICC line were noted among 6 of 23 (26.1%) patients given IV ceftriaxone and among 1 of 14 (7.1%) patients given IV placebo; these resolved without permanent injury. CONCLUSION: IV ceftriaxone therapy results in short-term cognitive improvement for patients with posttreatment Lyme encephalopathy, but relapse in cognition occurs after the antibiotic is discontinued. Treatment strategies that result in sustained cognitive improvement are needed.

Neuroendocrine predictors of response to intravenous clomipramine therapy for refractory obsessive-compulsive disorder.

The current study examines the neuroendocrine response to intravenous clomipramine (IV CMI) in oral CMI-resistant obsessive-compulsive disorder (OCD) patients on day 1 and day 14 of treatment to identify predictors of response. Forty-four OCD patients with an inadequate response or poorly tolerant to oral CMI were begun at 25 mg IV CMI, increasing to 250 mg by day 10, and continuing on that dose to day 14. On day 1, plasma levels of prolactin (PRL), growth hormone (GH), and cortisol were obtained immediately before the 25 mg IV infusion, and at five 30-minute time points after the infusion. On day 14, hormonal samples were obtained in a similar fashion. Response was assessed by the Clinical Global Impressions (CGI). Low PRL(MAX) to IV CMI and low cortisol levels overall on day 1 were both significantly associated with clinical response at day 14. An overall increase in growth hormone (GH) secretion during the day 14 testing was associated with positive response. A pronounced PRL response to IV CMI on day 14 was exhibited by the nonresponders, whereas a smaller and later but significant increase in PRL was noted in the responders. The findings suggest that in this sample of oral CMI-resistant patients with OCD, neuroendocrine measures derived from pharmacological challenge with IV CMI are capable of distinguishing IV CMI treatment responders from nonresponders. The limitations of IV CMI as a specific probe of serotonin function are discussed.

A controlled study of cognitive deficits in children with chronic Lyme disease.

Although neurologic Lyme disease is known to cause cognitive dysfunction in adults, little is known about its long-term sequelae in children. Twenty children with a history of new-onset cognitive complaints after Lyme disease were compared with 20 matched healthy control subjects. Each child was assessed with measures of cognition and psychopathology. Children with Lyme disease had significantly more cognitive and psychiatric disturbances. Cognitive deficits were still found after controlling for anxiety, depression, and fatigue. Lyme disease in children may be accompanied by long-term neuropsychiatric disturbances, resulting in psychosocial and academic impairments. Areas for further study are discussed.

Canadian Incidence Study of Reported Child Abuse and Neglect: methodology.

This article describes the methodology of the first Canada-wide study of the incidence and characteristics of reported child abuse and neglect. Child welfare investigators from a random sample of 51 child welfare service areas completed a three-page survey form describing the results of 7,672 child maltreatment reports received during the months of October to December 1998. The study documented a 90% participation rate and a 95% item completion rate. An estimated 135,571 child maltreatment investigations were completed, a rate of 21.52 investigated children per 1,000 children in Canada in 1998. The Canadian Incidence Study of Reported Child Abuse and Neglect is a rich database that will provide researchers with important contextual information on reported child maltreatment in Canada and a comprehensive source of information on factors associated with key service decisions made by child welfare investigators.

Therapeutic approaches to the treatment of refractory obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a debilitating condition that afflicts approximately 1% to 3% of the world population. The primary treatments are selective serotonin reuptake inhibitors and behavioral therapy. Despite therapy, approximately 30% to 40% of patients continue to suffer from disabling OCD symptoms. This article addresses the range of treatment options for patients with refractory OCD, focusing upon novel strategies and the most recent research.

Hypochondriasis and its relationship to obsessive-compulsive disorder.

Hypochondriasis is a heterogeneous disorder. This was well demonstrated in the study by Kellner et al, which showed that patients with high levels of disease fear tended to be more anxious or phobic, whereas patients with high levels of disease conviction tended to have more and more severe somatic symptoms. Little comorbidity exists to support the statement that hypochondriasis is an obsessive-compulsive spectrum disorder. Although patients exist whose hypochondriac concerns are identical in quality to the intrusive thoughts of patients with OCD, as a group, patients with hypochondriasis do not share a comorbidity profile comparable with that of patients with OCD. The data support a closer relationship between hypochondriasis and somatization disorder than between hypochondriasis and OCD. The family history data is limited by the lack of adequate studies. Using comparable methods of the family history approach, Black's study reported a higher frequency of GAD but not OCD among the relatives of OCD patients--a finding similar to what Noyes found among the relatives of hypochondriac patients; however, using the direct interview method, somatization disorder was the only statistically more common disorder, among relatives of female hypochondriac patients. Therefore, although the parallel in overlap with GAD is suggestive of a commonality between OCD, GAD, and hypochondriasis, the finding of a greater frequency of somatization disorder leans against the hypothesis that hypochondriasis is best considered an OCD spectrum disorder. The pharmacologic treatment data are the one type of biologic evidence that supports a bridge to OCD. The pharmacologic studies suggest that for patients with general hypochondriasis, TCAs are not effective and that higher dosages and longer trials of the SRIs are needed. These pharmacologic observations are comparable with the ones made for patients with OCD but dissimilar to the observations made for depression. The benefit of imipramine among patients with illness phobia must be assessed in placebo-controlled trials among illness phobics and among hypochondriacs. Even more valuable would be a direct comparison of a TCA (e.g., imipramine or desipramine) and a selective SRI (e.g., fluoxetine) to determine whether the response to selective SRIs is greater. Although the pharmacologic data are compelling in supporting the hypothesis that hypochondriasis is an obsessive-compulsive spectrum disorder, the comorbidity data are equally compelling in dispelling that hypothesis. Perhaps future studies clarify the subtypes of hypochondriasis, be they "phobic, obsessive, and depressive," "chronic and episodic," "early onset versus late onset" or some other as yet undetermined subtype. Such clarification may be aided by better instruments to assess the obsessive-compulsive and hypochondria spectrums within individuals and families and by neuropsychological or pharmacologic challenge and neuroimaging studies.

Obsessive-compulsive disorder: an overview.

In this article, which is the first in a three-part series, the authors provide an overview of the current state of our knowledge of the phenomenology, etiology, and diagnosis of OCD. The DSM-IV criteria for OCD are presented and explicated. Disorders that are commonly comorbid with OCD (e.g., major depressive disorder, other anxiety dis-orders, Tourette's disorder) are described. The authors also discuss disorders such as body dysmorphic disorder that may be related to OCD and are often termed OCD spectrum disorders. OCD is likely to have multiple causes and the authors discuss behavioral, neuroanatomical, and neurochemical theories of OCD. Two treatments have demonstrated efficacy in OCD, cognitive-behavioral therapy and pharmacotherapy with serotonergic reuptake inhibitors, and the authors discuss how these treatments may work in light of what is known about the etiology of the disorder. The different subtypes of OCD that have been proposed are described along with their implications for treatment. The article concludes with a discussion of diagnosis that provides specific guidance for the clinician on how to assess a patient for possible OCD. The next two articles in this series will cover cognitive-behavioral and medication treatment in detail.

Biological therapies for obsessive-compulsive disorder.

Two treatments have demonstrated efficacy in OCD, exposure and response (ritual) prevention (EX/RP) and pharmacotherapy with serotonin reuptake inhibitors (SRIs). In this article, which is the third in a three-part series, the authors present an overview of the role of biological treatments for OCD. The evidence for the efficacy of the serotonin reuptake inhibitors (clomipramine and the five selective serotonin reuptake inhibitors "SSRIs" fluvoxamine, fluoxetine, paroxetine, sertraline, and citalopram) as monotherapy for OCD is reviewed. The authors also discuss the rationale for choosing among these agents for specific patients. Research on other types of medication monotherapies for OCD is also discussed. The authors then cover strategies for treatment-resistant OCD, including combining EX/RP and SRI medication treatment, combining clomipramine and an SSRI, use of augmenting medications, and use of intravenous clomipramine. Findings concerning the use of other somatic therapies for treatment-resistant OCD, including electroconvulsive therapy, neurosurgery, plasma exchange/IV immunoglobulin/maintenance antibiotics, and transcranial magnetic stimulation, are also reviewed. Finally, the authors discuss what is known about matching treatments to patients with certain specific symptom clusters, how long to continue maintenance medication treatment, and how to terminate treatment.

Carbamazepine in the treatment of Lyme disease-induced hyperacusis.

Lyme disease-induced hyperacusis can be an intensely disabling, chronic condition that is accompanied by posttraumatic stress disorder-like psychobehavioral sequelae. The authors describe effective treatment of 2 patients with carbamazepine. Speculations regarding a mode of action are offered.

The underdiagnosis of neuropsychiatric Lyme disease in children and adults.

Lyme Disease has been called "The New Great Imitator," a replacement for that old "great imitator" neurosyphilis. This article reviews the numerous psychiatric and neurologic presentations found in adults and children. It then reviews the features of Lyme Disease, which makes it almost uniquely hard to diagnose, including the complexity and unreliability of serologic tests. Clinical examples follow that illustrate those presentations of this disease that mimic attention deficit hyperactivity disorder (ADHD), depression, and multiple sclerosis.

Intravenous clomipramine for obsessive-compulsive disorder refractory to oral clomipramine: a placebo-controlled study.

BACKGROUND: Uncontrolled reports suggest that intravenous clomipramine hydrochloride may be effective for patients with obsessive-compulsive disorder (OCD) who are nonresponsive to oral clomipramine. METHODS: Fifty-four patients with oral clomipramine-refractory OCD were randomized to receive 14 infusions of either placebo or clomipramine hydrochloride, starting at 25 mg/d and increasing to 250 mg/d. Ratings were conducted double-blind after infusion 14 among 54 patients, single-blind 1 week later among 39 patients, and nonblind 1 month later among 31 patients. Response was based on a Clinical Global Impressions rating of at least "much improved." RESULTS: Six (21%) of 29 patients randomized to receive intravenous (i.v.) clomipramine vs 0 of 25 patients given i.v. placebo were responders after 14 infusions (df = 1, P<.02). Dimensional ratings after infusion 14 revealed significant (P = .007) improvement on the National Institute of Mental Health-Obsessive-Compulsive Scale and the Clinical Global Impressions Scale (P = .03), but not the Yale-Brown Obsessive Compulsive Scale. One week later, all dimensional measures of OCD showed significant improvement. At 1 week post-i.v., 9 (43%) of 21 patients initially randomized to i.v. clomipramine and treated subsequently with oral clomipramine were responders, whereas 0 of 18 patients initially randomized to receive i.v. placebo and treated subsequently with several days of open-label i.v. clomipramine responded (df = 1, P<.002). Of the 31 patients assessed 1 month after i.v. infusion (treatment not controlled), 18 (58.1%) were responders. Intravenous clomipramine treatment was safe with no serious adverse consequences. CONCLUSIONS: Intravenous clomipramine is more effective than i.v. placebo for patients with OCD with a history of inadequate response or intolerance to oral clomipramine. Further study of this promising treatment for refractory OCD is needed.

Imipramine in the treatment of social phobia.

We report the results of an 8-week open trial of imipramine in 15 patients with social phobia. Nine patients completed the trial; six dropped out early because of adverse effects. The mean reduction in the Liebowitz Social Anxiety Scale was 15% and 18% for the intent-to-treat and completer groups, respectively; the overall response rate (based on the Clinical Global Impression Scale of 1 or 2, very much or much improved) was 20% (3/15) and 22% (2/9), respectively. The results from this open trial do not support the efficacy of imipramine as a treatment for social phobia.

An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder.

The symptom overlap between posttraumatic stress disorder (PTSD) and other pharmacotherapy-responsive disorders suggests that pharmacotherapy might be effective. Nevertheless, of the eight published placebo-controlled trials investigating the pharmacotherapy of PTSD, only four found statistically significant efficacy for the treatment being studied. This literature possesses a number of methodologic limitations, including the fact that most studies have been conducted with war veterans, who may constitute a more treatment-refractory population. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in some or all core PTSD symptoms (reexperiencing, avoidance, numbing, and hyperarousal). The authors hypothesized that paroxetine might be effective in PTSD, based on findings of its particular efficacy for anxiety and agitation in studies of depressed patients. The study presented here summarizes a 12-week, open-label trial of paroxetine among patients with noncombat-related, chronic PTSD. Outcome was assessed by an independent evaluator, the treating physician, and the patient, with the use of established rating scales for depression, anxiety, general symptoms, and PTSD core symptoms. A repeated-measures analysis of variance revealed highly significant improvement in all three symptom clusters, as well as in associated anxiety, depressive, and dissociative symptoms, with 11 of 17 (65%) patients rated as much or very much improved. The mean reduction in PTSD symptom scores was 48%. Exploratory analyses revealed that cumulative childhood trauma was negatively correlated with pharmacotherapy response (r = -0.52, p = 0.03). There was also significant variation in the time course of response across symptom clusters, which is suggestive of multiple mechanisms of response. Because paroxetine seems a highly promising treatment for all three symptom clusters of PTSD, a placebo-controlled clinical trial is warranted.

Clomipramine treatment of panic disorder: pros and cons.

BACKGROUND: Controlled trials suggest that clomipramine may be a highly effective antipanic drug. Lowering the starting dose may alleviate troublesome initial side effects and increase acceptability and compliance. METHOD: Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment. Starting at 10 mg/day, the dose was gradually increased to a mean dose of 97 mg/day. RESULTS: While completers showed highly significant improvement, the benefits were severely limited by a high dropout rate due to adverse reactions occurring mostly during the first 2 weeks of treatment. CONCLUSION: Given the alternatives, clomipramine should not be used as a first-line antipanic medication.

Functional brain imaging and neuropsychological testing in Lyme disease.

Differentiating neuropsychiatric Lyme disease from a primary psychiatric disorder can be a daunting task. This article describes how functional brain imaging and neuropsychological testing can be particularly valuable in helping to make diagnostic distinctions. In addition to a review of the relevance of functional imaging to neuropsychiatry in general, recent findings are presented regarding the use of single photon emission computed tomographic (SPECT) imaging in Lyme disease.

The pharmacotherapy of hypochondriasis.

This article addresses the diagnosis and pharmacologic treatment of hypochondriasis. Diagnostic issues are reviewed briefly, focusing on the need for a thorough medical re-consideration of the patient's presenting symptoms. Because the diagnosis rests on the absence of a medical cause to account for the presence or intensity of the physical symptoms, neither self-report forms nor non-medically trained interviewers should be used to definitively make the diagnosis of hypochondriasis. We review the case reports and small uncontrolled series on the pharmacologic treatment of hypochondriasis, emphasizing the growing body of evidence suggesting particular efficacy for the serotonin reuptake inhibitors. Preliminary results from an ongoing placebo-controlled trial of hypochondriasis using fluoxetine are presented. While the controlled trial supports the open treatment data in revealing a high rate of improvement among patients completing treatment with fluoxetine, it also demonstrates that many patients respond to placebo as well. In conclusion, although the traditional nihilistic attitude regarding the possibility of successful treatment of hypochondriacs appears no longer warranted, the question remains open as to whether SSRIs have particular efficacy in patients with hypochondriasis or whether nonspecific treatment effects are the primary cause of improvement.

Lyme disease: a neuropsychiatric illness.

OBJECTIVE: Lyme disease is a multisystemic illness that can affect the central nervous system (CNS), causing neurologic and psychiatric symptoms. The goal of this article is to familiarize psychiatrists with this spirochetal illness. METHOD: Relevant books, articles, and abstracts from academic conferences were perused, and additional articles were located through computerized searches and reference sections from published articles. RESULTS: Up to 40% of patients with Lyme disease develop neurologic involvement of either the peripheral or central nervous system. Dissemination to the CNS can occur within the first few weeks after skin infection. Like syphilis, Lyme disease may have a latency period of months to years before symptoms of late infection emerge. Early signs include meningitis, encephalitis, cranial neuritis, and radiculoneuropathies. Later, encephalomyelitis and encephalopathy may occur. A broad range of psychiatric reactions have been associated with Lyme disease including paranoia, dementia, schizophrenia, bipolar disorder, panic attacks, major depression, anorexia nervosa, and obsessive-compulsive disorder. Depressive states among patients with late Lyme disease are fairly common, ranging across studies from 26% to 66%. The microbiology of Borrelia burgdorferi sheds light on why Lyme disease can be relapsing and remitting and why it can be refractory to normal immune surveillance and standard antibiotic regimens. CONCLUSIONS: Psychiatrists who work in endemic areas need to include Lyme disease in the differential diagnosis of any atypical psychiatric disorder. Further research is needed to identify better laboratory tests and to determine the appropriate manner (intravenous or oral) and length (weeks or months) of treatment among patients with neuropsychiatric involvement.

Childhood abuse, family environment, and outcome in bulimia nervosa.

BACKGROUND: About one third of patients with bulimia nervosa continue to do poorly despite intensive treatment. In an effort to identify historical factors that might differentiate patients who are persistently bulimic from patients who have fully recovered, we examined the relationship between long-term outcome and three factors: childhood trauma, family environment, and parental psychopathology. METHOD: Fifty-two women previously hospitalized for bulimia nervosa were interviewed 2 to 9 years later. In addition to structured diagnostic interviews, measures included the Family Environment Scale, the Family History interview, and a semistructured interview of childhood abuse. Outcome comparisons were made between the fully recovered and the women who still met DSM-III-R criteria for bulimia nervosa. RESULTS: Reports of childhood physical abuse and of a family environment characterized by low cohesion and high control were significantly associated with poor outcome. Characteristics of the family environment seemed to have greater influence on outcome than physical abuse alone. Sexual abuse in general was not associated with outcome. Outcome was not associated with comorbidity of Axis I or Axis II disorders or parental psychopathology. CONCLUSION: Aspects of the family environment of childhood may contribute to the course of bulimia nervosa. Definitive conclusions require a prospective study.