Christopher L. Sola

Serial infusions of low-dose ketamine for major depression

Background: Single infusions of ketamine have been used successfully to achieve improvement in depressed patients. Side effects during the infusions have been common. It is not known whether serial infusions or lower infusion rates result in greater efficacy. Methods: Ten depressed patients were treated with twice weekly ketamine infusions of ketamine 0.5 mg/kg administered over 100 min until either remission was achieved or four infusions were given. Side effects were assessed with the Young Mania Rating Scale (YMRS) and the Brief Psychiatric Rating Scale (BPRS). Patients were followed naturalistically at weekly intervals for four weeks after completion of the infusions. Results: Five of 10 patients achieved remission status. There were no significant increases on the BPRS or YMRS. Two of the remitting patients sustained their improvement throughout the four week follow-up period. Conclusions: Ketamine infusions at a lower rate than previously reported have demonstrated similar efficacy and excellent tolerability and may be more practically available for routine clinical care. Serial ketamine infusions appear to be more effective than a single infusion. Further research to test relapse prevention strategies with continuation ketamine infusions is indicated.

Implantable cardioverter-defibrillators, induced anxiety, and quality of life.

Since its approval in 1985, the implantable cardioverter-defibrillator (ICD) has supplanted antiarrhythmic drugs as the standard of care for patients with potentially lethal ventricular arrhythmias. The increased popularity of ICDs stems primarily from their safety and tolerability compared with commonly used medications notorious for adverse drug reactions. As ICD indications have broadened, the number of implantations has increased substantially, and more attention has been directed to sequelae of implantation, particularly after ICD firing. Although scant, studies of quality of life and psychiatric symptoms in patients with ICDs consistently report assorted psychiatric disturbances affecting up to 87% of recipients. Depression and anxiety predominate: up to 38% of patients experience symptoms that meet diagnostic criteria for an anxiety disorder. Psychological theories such as the classic conditioning model, learned helplessness model, and cognitive appraisal model have been invoked to conceptualize these new-onset ICD-induced anxiety disorders. Small trials of psychosocial interventions, including support groups and cognitive behavioral therapy, have had mixed results. Little is known about preexisting anxiety disorders in ICD recipients, particularly which premorbid features predict a worse prognosis, other than suggestions that younger patients and those receiving multiple shocks are at greater risk. Prospective studies of the psychopathology of patients with ICDs, both before and after implantation, are warranted.

Management of psychiatric symptoms in anti-NMDAR encephalitis: a case series, literature review and future directions

Anti-NMDA receptor (NMDAR) encephalitis, formally recognized in 2007, has been increasingly identified as a significant cause of autoimmune and paraneoplastic encephalitis. Approximately 80% of the patients are females. The characteristic syndrome evolves in several stages, with approximately 70% of the patients presenting with a prodromal phase of fever, malaise, headache, upper respiratory tract symptoms, nausea, vomiting and diarrhoea. Next, typically within two weeks, patients develop psychiatric symptoms including insomnia, delusions, hyperreligiosity, paranoia, hallucinations, apathy and depression. Catatonic symptoms, seizures, abnormal movements, autonomic instability, memory deficits may also develop during the course of the disease. Presence of antibodies against the GluN1 subunit of the NMDAR in the CSF and serum confirm the diagnosis of NMDAR encephalitis, which also should prompt a thorough search for an underlying tumor. Age, gender, and ethnicity may all play a role, as black females older than 18 years of age have an increased likelihood of an underlying tumor. Treatment is focused on tumor resection and first-line immunotherapy [corticosteroids, plasma exchange, and intravenous immunoglobulin]. In non-responders, second- line immunotherapy [rituximab or cyclophosphamide or combined] is required. More than 75% of the patients recover completely or have mild sequelae, while the remaining patients end up demonstrating persistent severe disability or death. There is a paucity of literature on the management of psychiatric symptoms in this population. Given the neuropsychiatric symptoms in the relatively early phase of the illness, approximately 77 % of the patients are first evaluated by a psychiatrist. Earlier recognition of this illness is of paramount importance as prompt diagnosis and treatment can potentially improve prognosis. We describe two patients diagnosed with NMDAR encephalitis presenting with two different psychiatric manifestations. The first patient presented with psychotic mania and catatonic symptoms, while the second suffered from depression with psychotic and catatonic features refractory to psychotropic medications. We review of the use of psychotropic medications and ECT to address insomnia, agitation, psychosis, mood dysregulation and catatonia in NMDAR encephalitis.

An Updated Review of Implantable Cardioverter/Defibrillators, Induced Anxiety, and Quality of Life

Despite overall favorable acceptance of implantable cardioverter-defibrillators (ICDs), patients may experience discharges as frightening and painful. The authors reviewed ICD-induced psychopathology in 2005. During the past 2 years the number of studies examining psychopathology and quality of life after ICD implantation has increased dramatically, warranting this update of that review. Variables assessed have included recipient age, gender, social support network, perception of control and predictability of shocks, and personality style. Now the picture of what is known is, if anything, cloudier than it was 2 years ago, with little definitive and much contradictory data emerging in most of these categories.

Anticipating Potential Linezolid-SSRI Interactions in the General Hospital Setting: An MAOI in Disguise

Linezolid, a novel antimicrobial with activity against gram-positive bacteria including pathogens resistant to traditional antimicrobials, also inhibits monoamine oxidase. This latter property can cause potentially lethal adverse interactions with antidepressant medications. Long known to psychiatrists, monoamine oxidase inhibitors (MAOIs) and complications of their use may be unfamiliar to medical and surgical practitioners who may thus unwittingly precipitate a hypertensive crisis or serotonin syndrome. We review the pharmacology of MAOis and describe 3 clinical situations In which linezolid-selective serotonin inhibitor (SSRI) interactions, actual or potential, figured prominently.

Familial Hemiplegic Migraine, Neuropsychiatric Symptoms, and Erdheim‐Chester Disease

We report the occurrence of unilateral cerebral hemisphere edema with subsequent cortical laminar necrosis in the setting of familial hemiplegic migraine (FHM) and permanent neurologic sequelae after resolution of an attack in 1 patient. Contemporaneous with this severe attack of FHM, the patient was found to exhibit multiple systemic and neurological symptoms referable to Erdheim‐Chester disease (a rare non‐Langerhans cell histiocytosis) that was confirmed by bone biopsy. This case demonstrates the severity possible with a migrainous infarction associated with FHM. The co‐occurrence of two such rare entities in 1 patient suggests a possible relationship.

Reconciling the risk of QT interval prolongation in antidepressants

We discovered your article1 as a result of seeking answers to the myriad of theoretical and practical questions raised in response to a recent Food and Drug Administration (FDA) decision regarding citalopram. This decision is based in part on after-market case reports to the FDA and in part on a randomized, multi-center, double-blind, placebo-controlled, crossover study of 119 subjects receiving citalopram 20mg per day (Day 9), citalopram 60mg per day (Day 22), and placebo. At 20mg per day, the average QTc (the interval between the beginning of an electrocardiographic QRS complex and the peak of the subsequent T wave, corrected for heart rate) was increased by 8.5milliseconds and at 60mg daily by 18.5milliseconds. Based on this, the FDA advised against the use of citalopram above 40mg daily. To quote, “As a result of this thorough QT study, the FDA has determined that citalopram causes dosedependent QT (the interval between the beginning of a QRS complex and the peak of the subsequent T wave) interval prolongation and should no longer be used at doses above 40mg per day.”2 There are two assumptions on which the FDA based their decision. The first is that there is no antidepressant dose–response relationship or benefit to increasing antidepressant dose. We acknowledge that based on the relative lack of dose response from the research, there are real and significant questions related to the clinical practice of increasing the dose in patients who demonstrate no response. The second assumption, however, is that the dose-related changes in the QT interval are clinically relevant and that they directly lead to increased rates of torsades de pointes (TdP) and sudden cardiac death. Your findings identified “. . .4222 sudden cardiac death and ventricular arrhythmia outcomes for a rate of 3.3/1000 personyears” for all antidepressants and found no evidence of an increased hazard ratio for citalopram as compared to paroxetine (or ten other antidepressants). This would seem to argue strongly against the FDA decision. Your work is consistent with an older large-scale trial (1460 adult and elderly patients with major depression and/or dementia) in which the authors demonstrated that “there were no significant effects on. . .QTc intervals, indicating that citalopram has no effect on cardiac conduction and repolarization”3 and a more recent trial comparing venlafaxine’s effect on sudden cardiac death compared to fluoxetine, dusolepin, and citalopram.4 We would argue strongly that the FDA assumption that dose-related QT interval prolongation for citalopram leads to TdP and sudden death is not valid based on your research reflecting that there is no difference in rates of sudden death. There are other factors that your article considered, including genetic factors associated with drug metabolism, and medical comorbidity, which the FDA did not consider. Citalopram, a generic drug, is cautioned against, but the FDA remains silent regarding its still-proprietary enantiomer, escitalopram. Similarly odd is the decision to single out citalopram, ignoring a wide variety of antidepressants, despite large-scale trials—yours included—demonstrating its relative safety. Based on this and on clinical use of the drug over the past 14 years with a generally favorable safety profile, psychiatrists and other prescribers have met the FDA’s advisory with consternation, questioning the decision-making process. We recognize that QT prolongation can be potentially concerning but feel strongly that it must be considered in context. As the authors of a review of drug-induced arrhythmia stated, “it would be possible for regulatory bodies to reduce but not eliminate entirely the risk of TdP by declining to approve any drug with the potential to prolong the QTc interval, even to a modest degree. Although intuitively appealing, this approach inevitably would harm the public interest by denying patients access to many therapeutic agents whose proven clinical benefit far outweighs their arrhythmic risk (which in many instances is theoretical and based only on a modest potential for QTc prolongation).”5 This calls to attention the risk–benefit ratio of medications as a whole and cautions against the current FDA decision.

Catatonia as a manifestation of tacrolimus-induced neurotoxicity in organ transplant patients: A case series

Tacrolimus has been associated with severe neurotoxicity in organ transplant patients. Catatonia can be a rare manifestation of tacrolimus-induced neurotoxicity as we report two cases of catatonia in solid organ transplant patients on tacrolimus. Catatonic symptoms completely resolved in these patients after reducing the tacrolimus dosage or switching it to alternative immunosuppressants. Catatonia symptoms in organ transplant patients should alert clinicians to look for tacrolimus-induced neurotoxicity despite normal serum tacrolimus levels and neuroimaging findings.

Voltage-Gated Potassium Channel-Complex Antibody-Associated Limbic Encephalitis

Limbic encephalitis is characterized by the subacute progression of short-term memory loss, disorientation, confusion, and agitation. Hallucinations, behavioral and personality changes, temporolimbic seizures, sleep disturbances, and dysautonomia may also occur. The pyramidal layer of the hippocampus and the amygdaloid nuclei are particularly susceptible and demonstrate neuronal loss, reactive gliosis, and perivascular lymphocytic cuffing. Magnetic resonance imaging (MRI) typically reveals increased signal in limbic structures on T2, fluid-attenuated inversion recovery (FLAIR), and diffusion-weighted imaging (DWI). Historically, limbic encephalitis has been conceptualized as a paraneoplastic process characterized by autoantibodies associated with underlying neoplasms: small cell lung, lymphoma, thymoma, testicular, breast, teratoma, prostate, rectal, retinoblastoma, oligodendroglioma, melanoma, and leiomyosarcoma. Although a definitive pathophysiologic mechanism for autoimmune limbic encephalitis remains unknown, multiple autoantibodies are implicated, including voltage-gated potassium channel complex antibodies (VGKC-complex Ab.) Idiopathic autoimmune limbic encephalitis also occurs. We present the longitudinal course of a man who developed cognitive and behavioral disturbances ultimately attributed to VGKC complex autoimmunity.

Successful use of ECT in post-stroke depression.

Post-stroke depression is a potentially persistent complication of stroke. Electroconvulsive therapy (ECT) is an effective treatment for depression, but with limited data regarding safety in stroke patients. We report the case of a 30-year-old woman with a history of stroke and antiphospholipid syndrome, who became depressed and suicidal. Neurologic and Internal Medicine consults did not reveal any contraindications to ECT, but stroke risk factor management was identified as an important measure for patient safety. The patient tolerated ECT well, reporting improvement of mood and abatement of hopelessness. This case suggests that ECT may be a safe and well-tolerated treatment for post-stroke depression.