Markus A. Kölle

Delusional infestation: neural correlates and antipsychotic therapy investigated by multimodal neuroimaging.

INTRODUCTION In delusional infestation (DI), as with other non-schizophrenic psychotic disorders, little is known about the neural basis and the mechanisms of antipsychotic treatment. We aimed at investigating the brain circuitry involved in DI and the role of postsynaptic D2 receptors in mediating the effects of antipsychotics by means of multimodal neuroimaging. METHODS In Case 1, a patient with DI (initially drug-induced), cerebral glucose metabolism and dopaminergic neurotransmission were studied in the untreated state (FDG-PET, FDOPA-PET, 123I-FP-CIT-SPECT, and IBZM-SPECT) and after effective aripiprazole treatment (FDG-PET and IBZM-SPECT), with negative drug screenings at both imaging sessions. In Case 2 (DI secondary to mild vascular encephalopathy) cerebral perfusion and gray matter volume changes were investigated in the untreated state and compared to N=8 [corrected] age-matched healthy controls (MRI-based CASL and VBM). RESULTS In Case 1, before treatment, glucose metabolism was left-dominant in the thalamus and the putamen. Pre- and postsynaptic dopaminergic neurotransmissions were altered in the striatum, again mainly the left putamen. Full remission to aripiprazole was associated with 63 to 78% striatal D2 receptor occupancy and glucose metabolism changes in the bilateral thalamus. In Case 2, significant perfusion and GMV changes were observed in the bilateral putamen, frontal and parietal somatosensory cortices as compared to controls. Symptoms partially remitted to ziprasidone therapy. DISCUSSION/CONCLUSION Six imaging techniques were first used to study the neural basis of DI and mechanisms of antipsychotic therapy. The study provides first low-level evidence in vivo evidence of fronto-striato-thalamo-parietal network to mediate core symptoms of DI, i.e. a priori brain regions involved in judgment (frontal cortex), sensory gating (thalamus) and body perception (dorsal striatum, thalamus and somatic cortices). This is also the first report of effective treatment with aripiprazole in drug-induced DI and with ziprasidone in organic DI, adding to existing limited evidence that SGAs are helpful in various forms of DI. Effective antipsychotic treatment seems to depend on blocking striatal D2 receptors with similar occupancy rates as in schizophrenia. Larger samples are needed to confirm our preliminary findings and further evaluate their relevance for the different forms of DI.

Concerns About Pregabalin: Further Experience With Its Potential of Causing Addictive Behaviors

Pregabalin (PRG) is approved for the treatment of neuropathic pain, partial seizures, and generalized anxiety disorder in many countries. Supported by case reports and a few studies there is an ongoing debate on PRGs potential to cause addictive behaviors. Considering that PRG is currently under investigation for the treatment of benzodiazepine dependence and withdrawal as well as relapse prevention in alcohol dependence, assessment of PRGs abuse and dependence potential is indispensable. We report the case of a 38-year-old female patient with borderline personality disorder and past alcohol abuse who developed PRG abuse. The patient took up to 800 mg PRG per day, initially administered to treat unspecific anxiety, and experienced euphoric feelings after PRG intake. In the further course, she increased the daily PRG dosage and consulted other physicians to receive additional PRG prescriptions. During reduction of PRG, the patient developed a moderate withdrawal syndrome with vegetative symptoms. Because of the early detection of the developing PRG abuse (4 months after first application of PRG), the development of PRG dependence was prevented. This case illustrates the possibility of PRG to trigger the development of addictive behaviors and should encourage physicians to be very careful when administering PRG to patients with current or past substance-related disorders.

Delusional parasitosis and the matchbox sign revisited: the international perspective.

© 2010 The Authors. doi: 10.2340/00015555-0909 Journal Compilation

Abuse of methylphenidate in Germany: data from spontaneous reports of adverse drug reactions.

To retrieve insights into abuse/dependence of methylphenidate (MPH) in Germany, a query of a pharmacovigilance database was performed (observation interval: 1993 until 2012). From 1190 reports of any ADR related to MPH, n=23 (2%) cases of MPH abuse were identified (mean age 29 years; male sex 78%; mean daily MPH-dosage 111 ± 126.6 mg). As oral application was predominant (70%), the majority of reported cases of MPH abuse might be due to pharmacologic neuroenhancement.

Paliperidone extended-release: does it have a place in antipsychotic therapy?

Paliperidone (9-hydroxy-risperidone), the active metabolite of risperidone, was approved for treating schizophrenia worldwide in 2006 as paliperidone extended-release (PER), and became the first second-generation antipsychotic specifically licensed for treating schizoaffective disorder in 2009. However, at the same time, its comparatively high cost gave rise to concerns about the cost-effectiveness of PER as compared with its precursor, risperidone. This paper reviews the existing knowledge of the pharmacology, kinetics, efficacy, tolerability, and fields of application of PER, and compares PER with risperidone in order to determine whether it has a place in antipsychotic therapy. An independent assessment of all relevant publications on PER published until July 2010 was undertaken. PER has a unique pharmacological profile, including single dosing, predominantly renal excretion, low drug–drug interaction risk, and differs from risperidone in terms of mode of action and pharmacokinetics. High-level evidence suggests that PER is efficacious and safe in schizophrenia, schizoaffective disorder, and acute manic episodes. There is a striking lack of published head-to-head comparisons between PER and risperidone, irrespective of indication. Low-level evidence shows a lower risk for hyperprolactinemia and higher patient satisfaction with PER than with risperidone. PER adds to the still limited arsenal of second-generation antipsychotics. In the absence of direct comparisons with risperidone, it remains difficult to come to a final verdict on the potential additional therapeutic benefits of PER which would justify its substantially higher costs as compared with risperidone. However, in terms of pharmacology, the available evidence cautiously suggests a place for PER in modern antipsychotic therapy.

Self-mutilation induced by psychotropic substances: a systematic review.

Self-mutilation (SM) not only occurs among patients with schizophrenia, personality disorders or transsexuality but also as a phenomenon induced by psychotropic substances (PS). We intended to find characteristics of patients at risk to perform SM induced by PS (SMIPS), frequent PS within this phenomenon and typical presentations of SMIPS. A systematic review of the literature (including Medline, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials and Scopus) was conducted. On October 2011 we identified 26 cases (23 publications) of SM related to PS. Majority of patients (85%) was male, mean age was 30 years (median 41 years). Seventy-three percent of patients developed SM subsequent to the use of one PS, 27% presented SM after the use of more than one PS. Alcohol (25%), hallucinogens (25%) and amphetamines (22%) were found most frequently among the reported substances. Major impairment was present in 80%. Our findings suggest male sex, young age, a previous history of abuse of PS and the current use of alcohol, hallucinogens or amphetamines to favour SMIPS.

Delusional infestation induced by piribedil add-on in Parkinson's disease.

Antiparkinsonian dopaminergic drugs increase the susceptibility to paranoid symptoms in many patients suff ering from Parkinson ’ s disease. Paranoid symptoms most often occur as visual, sometimes acoustical hallucinations. Abnormal tactile sensations and delusional infestation (DI) have only been described in a single case of Parkinson ’ s disease treated with L-DOPA and amantadine but not with piribedil. Conversely, DI is often induced by illicit dopaminergic drugs. Apart from dysfunctional dopaminergic neurotransmission the pathophysiology of DI is poorly understood. A case of Parkinson ’ s Disease with stable, but insuffi cient L-DOPA / decarboxylase inhibitor MAO-B-inhibitor treatment is described. The addition of piribedil led to marked DI, while previous additions of ropinirole and pramipexole had not. This is the fi rst report of delusional infestation induced by piribedil add-on in Parkinson ’ s disease and the second case of antiparkinsonian medication-induced DI in general. Piribedil ’ s stronger antagonism at central alpha2-receptors, as compared to ropinirole and pramipexole, and the resulting increased corticolimbic adrenergic neurotransmission and dopamine release best explain the formation of drug-induced DI in this case, carefully pointing to neural mechanisms beyond the dopamine system in this disorder.

Glucose modulates food-related salience coding of midbrain neurons in humans.

Although early rat studies demonstrated that administration of glucose diminishes dopaminergic midbrain activity, evidence in humans has been lacking so far. In the present functional magnetic resonance imaging study, glucose was intravenously infused in healthy human male participants while seeing images depicting low‐caloric food (LC), high‐caloric food (HC), and non‐food (NF) during a food/NF discrimination task. Analysis of brain activation focused on the ventral tegmental area (VTA) as the origin of the mesolimbic system involved in salience coding. Under unmodulated fasting baseline conditions, VTA activation was greater during HC compared with LC food cues. Subsequent to infusion of glucose, this difference in VTA activation as a function of caloric load leveled off and even reversed. In a control group not receiving glucose, VTA activation during HC relative to LC cues remained stable throughout the course of the experiment. Similar treatment‐specific patterns of brain activation were observed for the hypothalamus. The present findings show for the first time in humans that glucose infusion modulates salience coding mediated by the VTA. Hum Brain Mapp 37:4376–4384, 2016.

From benzodiazepine to pregabalin dependence: Different agents, similar problems

1. Gahr M, Franke B, Freudenmann RW, Kölle MA, Schönfeldt‐Lecuona C. Concerns about pregabalin: Further experience with its potential of causing addictive behaviors. J Addict Med 2013;7:147-9. 2. Schifano F. Misuse and abuse of pregabalin and gabapentin: Cause for concern? CNS Drugs 2014;28:491‐6. 3. Patorno E, Bohn RL, Wahl PM, Avorn J, Patrick AR, Liu J, et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA 2010;303:1401-9. 4. Yargic I, Ozdemiroglu FA. Pregabalin abuse: A case report. Bull Clin Psychopharmacol Bull 2011;21:64‐6. 5. Tandon VR, Mahajan V, Gillani ZH, Mahajan A. Pregabalin‐induced self‐harm behavior. Indian J Pharmacol 2013;45:638‐9. A 30‐year‐old married male was brought by his mother with a history of pregabalin dependence since 4 years. Patient was started on 75 mg of pregabalin for neuropathic pain in temporomandibular joint. As he experienced euphoria and increased energy levels after pregabalin consumption, his consumption increased to 20 capsules (equivalent to 1500 mg) at irregular intervals per day over the period of 1 year and since last 2 years his consumption increased to 40 capsules (equivalent to 3000 mg) per day due to tolerance to pregabalin. He would experience withdrawal symptoms such as palpitations, restlessness, and dysphoria on missing the doses.

Withdrawal and discontinuation phenomena associated with tranylcypromine: a systematic review.

Tranylcypromine (TCP) is an effective antidepressant with a complex pharmacological profile and a relevant risk of abuse and dependence. Withdrawal phenomena (WP, in the case of TCP-abuse/dependence) or discontinuation phenomena (DP, in the case of absent TCP-abuse/dependence) subsequent to abrupt termination of TCP are a potentially severe clinical syndrome. We conducted a systematic review of all previously published WP/DP cases following abrupt termination of TCP in order to identify typical clinical presentations and risk factors of WP/DP and frequency of TCP abuse or dependence within these patients. By searching the Medline and Scopus databases we identified n=25 cases (cohort WP: n=18, cohort DP: n=7). Delirium was found in n=13 patients (cohort WP: 10/55.6%; cohort DP: 3/42.9%), n=6 demonstrated WP/DP without delirium (WP: 6/33.3%; DP: 0/0%) and n=5 rapid relapse in depression (WP: 1/5.6%; DP: 4/57.1%). Mean time until development of WP/DP was 1.9 (WP) and 2.2 (DP) days. Mean duration of WP/DP was 5.7 (WP) and 11.3 (DP) days. All patients of cohort WP were described to feature TCP-abuse/dependence. Patients with delirium were on average older (41.8 years vs. 37.8 years) and featured higher mean prescribed (71.0 mg vs. 38.3 mg) and actually taken daily TCP dosages (285.8 mg vs. 187.7 mg). In conclusion, even termination of lower daily dosages of TCP may result in delirium. Thrombocytopenia features diagnostic value in patients with deliria of unknown etiology. TCP should be administered with great care, especially in dependence-prone patients.·