Catatonia in resource-limited settings: a case series and treatment protocol.

OBJECTIVE: The catatonic syndrome ("catatonia") is characterized by motor and motivation dysregulation and is associated with a number of neuropsychiatric and medical disorders. It is recognizable in a variety of clinical settings. We present observations from the treatment of four individuals with catatonia in Haiti and Rwanda and introduce a treatment protocol for use in resource-limited settings. METHODS: Four patients from rural Haiti and Rwanda with clinical signs of catatonia and a positive screen using the Bush-Francis Catatonia Rating Scale were treated collaboratively by general physicians and mental health clinicians with either lorazepam or diazepam. Success in treatment was clinically assessed by complete remittance of catatonia symptoms. RESULTS: The four patients in this report exhibited a range of characteristic and recognizable signs of catatonia, including immobility/stupor, stereotypic movements, echophenomena, posturing, odd mannerisms, mutism and refusal to eat or drink. All four cases presented initially to rural outpatient general health services in resource-limited settings. In some cases, diagnostic uncertainty initially led to treatment with typical antipsychotics. In each case, proper identification and treatment of catatonia with benzodiazepines led to significant clinical improvement. CONCLUSION: Catatonia can be effectively and inexpensively treated in resource-limited settings. Identification and management of catatonia are critical for the health and safety of patients with this syndrome. Familiarity with the clinical features of catatonia is essential for health professionals working in any setting. To facilitate early recognition of this treatable disorder, catatonia should feature more prominently in global mental health discourse.

Oxytocin interference in the effects induced by inhalation of 7.5% CO(2) in healthy volunteers.

OBJECTIVE: The objective of this study was to assess the acute effect of intranasally administered oxytocin (OT) on subjective states, cardiovascular, and endocrine parameters in healthy volunteers who inhaled 7.5% CO(2) . METHODS: Forty-five subjects were allocated into three matched groups of subjects who received 24 international units (IU) of OT, 2 mg of lorazepam (LZP), or placebo (PL). The challenge consisted of medical air inhalation for 20 min, 10 min of rest, and CO(2) 7.5% inhalation for 20 min. Subjective effects were evaluated by self-assessment scales; heart rate, blood pressure, skin conductance, and salivary cortisol were also measured. Assessments were performed at four time points: (i) baseline (-15 min); (ii) post-air inhalation (90 min); (iii) post-CO(2) inhalation (120 min), and (iv) post-test (160 min). RESULTS: CO(2) inhalation significantly increased the anxiety score in the PL group compared with the post-air measurement but not in the OT or LZP groups. The LZP reduced anxiety after medical air inhalation. Other parameters evaluated were not affected by OT. CONCLUSION: OT, as well as LZP, prevented CO(2) -induced anxiety, suggesting that this hormone has anxiolytic properties.

Effects of lorazepam on visual perceptual abilities.

OBJECTIVE: To evaluate the effects of an acute dose of the benzodiazepine (BZ) lorazepam in young healthy volunteers on five distinguishable visual perception abilities determined by previous factor-analytic studies. METHODS: This was a double-blind, cross-over design study of acute oral doses of lorazepam (2 mg) and placebo in young healthy volunteers. We focused on a set of paper-and-pencil tests of visual perceptual abilities that load on five correlated but distinguishable factors (Spatial Visualization, Spatial Relations, Perceptual Speed, Closure Speed, and Closure Flexibility). Some other tests (DSST, immediate and delayed recall of prose; measures of subjective mood alterations) were used to control for the classic BZ-induced effects. RESULTS: Lorazepam impaired performance in the DSST and delayed recall of prose, increased subjective sedation and impaired tasks of all abilities except Spatial Visualization and Closure Speed. Only impairment in Perceptual Speed (Identical Pictures task) and delayed recall of prose were not explained by sedation. CONCLUSION: Acute administration of lorazepam, in a dose that impaired episodic memory, selectively affected different visual perceptual abilities before and after controlling for sedation. Central executive demands and sedation did not account for results, so impairment in the Identical Pictures task may be attributed to lorazepam's visual processing alterations.

Effects of lorazepam on deductive reasoning.

RATIONALE: Benzodiazepines slow reasoning performance, but it is still unknown which phase of reasoning is affected and whether this effect is present for different types of relations between entities in reasoning problems. OBJECTIVES: We investigated which phases of deductive reasoning are affected by lorazepam and whether this effect varies according to the type of relations in deductive reasoning problems. METHODS: This was a double-blind, crossover design study of acute oral doses of lorazepam (2 mg) and placebo, using young healthy volunteers. We focused on response delay of three separable phases of deductive reasoning and matched working memory tasks (that involved only maintenance of information) the premise processing phase, the premise integration phase, and the validation phase, in which reasoners decide whether a conclusion logically follows from the premises (reasoning task) or is identical to one of the premises (maintenance task). Type of relations in the premises was also manipulated. We employed material that was difficult to envisage visually and visuospatially ("subiconic") and material easy to envisage visually or visuospatially. RESULTS: Lorazepam slowed response as memory load increased, irrespective of type of relations. It also specifically slowed validation in reasoning problems with visual relations, an effect that disappeared after subtraction of maintenance scores, and increased validation time in problems with subiconic relations, which remained after this subtraction. CONCLUSION: Acute lorazepam administration affected reasoning in two ways: it slowed processing nonspecifically when working memory demands increased and augmented validation time depending on the difficulty in generating and/or manipulating mental representations by the central executive.

Efficacy and tolerability of a standardized herbal product from Galphimia glauca on generalized anxiety disorder. A randomized, double-blind clinical trial controlled with lorazepam.

Galphimia glauca Cav. is a plant used in Mexican traditional medicine as a "nerve tranquilizer". Previous studies have demonstrated that the methanolic extract from this plant species possess an anxiolytic effect. Galphimine B (GB, a nor-seco-triterpene), is the active principle, with an innovative action mechanism. Against this background, a standardized herbal medicinal product was developed from the aqueous extract of G. glauca (GgHP). The present work compared the therapeutic effectiveness, safety, and tolerability of the new GgHP with lorazepam on patients with generalized anxiety disorder (GAD). By means of a controlled, randomized, double-blind clinical trial, outpatients of either sex who matched the DSM-IV diagnostic criteria with a score of > or = 19 points on the Hamilton Anxiety Scale (HAM-A) were included. The experimental group was treated orally with GgHP in capsules twice a day for 4 weeks. The control group received lorazepam (1 mg) under the same conditions and presentation. A total of 152 patients were included in the trial (72 in the experimental group). From the first week of treatment, GgHP showed important anxiolytic effectiveness, very similar to that produced with lorazepam. Both treatments showed therapeutic safety (no alterations on biochemical analysis of hepatic and renal function). Nevertheless, concerning side effects, GgHP evidenced a considerably higher tolerability than lorazepam.

Stem-completion tasks (indirect, direct inclusion and exclusion) are differently affected by equipotent doses of lorazepam and flunitrazepam.

This study was designed to explore the effects on performance in stem-completion tasks of two benzodiazepines (BZ) in equipotent doses: lorazepam, a drug that atypically disrupts perceptual priming, and flunitrazepam, a compound with standard BZ effects. The study followed a placebo-controlled, double-blind, parallel-group design. Thirty-six young and healthy subjects carried out three completion tasks at theoretical peak-plasma concentrations of drugs: (a) indirect tasks, in which the subjects were instructed to complete stems with the first word that came to mind; (b) direct inclusion tasks/cued recall, in which the participants had to try to use words seen at study as completions; and (c) direct exclusion tasks, in which words seen at study were to be avoided. The PDP was applied to the results in the inclusion and exclusion tasks, to obtain indices of explicit/controlled (C) and implicit/automatic (A) memory. The C index was lowered by both BZs and A was equivalent in all treatments, confirming the general amnestic action of BZs. However, lorazepam led to decreases in completions in the indirect and inclusion tasks, while flunitrazepam impaired performance in the exclusion task. The qualitative differences between the drugs in their effects on performance suggest that these BZs may lead to differences in response bias.

Adaptive changes in the rat hippocampal glutamatergic neurotransmission are observed during long-term treatment with lorazepam.

RATIONALE: Chronic treatment with benzodiazepines induces tolerance to most of their pharmacological effects. The best-studied neurochemical correlation to this phenomenon involves GABAergic adaptive changes. However, some compensation by excitatory neurotransmission could also be postulated. OBJECTIVE: The aim of this work was to investigate the effect of chronic treatment with benzodiazepines on several parameters of hippocampal glutamatergic neurotransmission. METHODS: Rats were injected (IP) with a single dose or daily doses (21 days) of 1 mg/kg lorazepam (LZ) or vehicle. Thirty minutes after the last dose, animals were killed and parameters were measured in the dissected hippocampi. We determined one presynaptic parameter, in vitro glutamate release induced by a 60 mM K(+) stimulus. [(3)H]MK-801 binding to postsynaptic NMDA receptors and the NMDA-stimulated efflux of cGMP were also evaluated. RESULTS: While no changes were observed in any of the parameters after a single dose of the drug, we found an increase of 206% in in vitro glutamate release in chronically treated animals [two-way ANOVA: F(1,16)=6.22], together with an increment of 103% in the NMDA-stimulated cGMP efflux [two-way ANOVA: F(1,18)=14.05]. No changes either in K(D) or in B(max) values for [(3)H]MK-801 binding to hippocampal membranes were observed. CONCLUSIONS: Taken together, these changes strongly suggest that a compensatory increase in the glutamatergic response develops in the hippocampus during chronic treatment with LZ. Our findings might indicate a contribution of glutamatergic mechanisms to the tolerance to hippocampal-mediated effects of LZ, such as amnesic and anticonvulsant activities.

Tolerance to the sedative effect of lorazepam correlates with a diminution in cortical release and affinity for glutamate.

Benzodiazepines are anxiolytic, anticonvulsant, sedative and hypnotic compounds usually prescribed on a long-term basis. Chronic treatment with these compounds induces tolerance, which has been extensively attributed to modifications in the GABAergic neurotransmission. However, a compensatory increase in the excitatory response, named as an oppositional response, has also been put forward as a means for explaining such tolerance. Changes in the excitatory neurotransmission have been found in withdrawn rats after a long treatment with benzodiazepines but these modifications have not been conclusively studied during tolerance. In this work we studied several parameters of the glutamatergic neurotransmission in rats made tolerant to the sedative effect of 3 mg/kg (i.p.) of lorazepam (LZ). We found a decrease in the affinity of cortical NMDA receptors for (3)H-glutamate (K(D): 124.4 +/- 13.3 nM in tolerant rats, 71.6 +/- 10.4 nM in controls, P<0.05) together with a decrease in the in vitro 60 mM K(+)-stimulated cortical glutamate release (59+/- 12% vs. 153 +/- 38%, tolerant rats vs. controls, P<0.05). We conclude that tolerance to the sedative effect of LZ correlates with a decreased sensitivity for glutamate that may in turn diminish the cortical response to a chemical stimulus. Our findings constitute an evidence against the oppositional model of pharmacodynamic tolerance in this experimental condition.

A double-dissociation of behavioural and event-related potential effects of two benzodiazepines with similar potencies.

This study was designed to explore the role of benzodiazepine affinity to benzodiazepine binding site on acute psychomotor, subjective and memory effects, as well as auditory Event Related Potential (ERP) latencies, in healthy volunteers. Two benzodiazepines with similar affinity to benzodiazepine binding sites, or potency, were compared: the atypical compound lorazepam (2.0 mg), which has been reported to impair priming, and a standard benzodiazepine, flunitrazepam (0.6 mg, 0.8 mg, 1.0 mg). The study followed a placebo-controlled, double-blind, parallel-group design. Sixty subjects completed a test battery before treatment and at theoretical peak plasma concentration of drugs. Lorazepam and 1.0 mg of flunitrazepam led to comparable alterations on psychomotor, subjective and auditory episodic memory measures. A double-dissociation was found for lorazepam and the equipotent dose of flunitrazepam (1.0 mg): lorazepam was more deleterious than flunitrazepam in time taken to identify fragmented shapes. Lorazepam also impaired direct and indirect stem-completion in comparison to placebo, but this effect was abolished when time to identify shapes was used as a covariate. By contrast, 1.0 mg of flunitrazepam prolonged auditory ERP latencies to a greater extent than lorazepam. High affinity to the benzodiazepine binding sites does not seem to explain the consistent lorazepam-induced impairment of indirect stem-completion. Differences in impairment profile between the benzodiazepines employed may relate to the modality (visual or not) of the tasks used.

Efecto agudo del lorazepam sobre los musculos respiratorios en los pacientes con EPOC estable / Acute effect of lorazepam on respiratory muscles in stable patients with chronic obstructive pulmonary disease

Con el objetivo de aclarar los efectos de las benzodiacepinas sobre los músculos respiratorios en pacientes con sobrecarga crónica de los mismos debida a enfermedad pulmonar obstructiva crónica (EPOC), se estudiaron 9 pacientes estables con EPOC avanzado (volumen espiratorio forzado en 1 segundo - FEV 1- 0,91 + 0,31 litros), en quienes, antes y 1 hora después de la administración de lorazepam 1,5 a 2 mg por vía sublingual, se evaluaron la capacidad vital forzada (FVC), FEV 1, ventilación voluntaria máxima (MVV), presión arterial de oxígeno (PaO2), presión arterial de anhídrido carbónico (PaCO2), volumen corriente (Vt), frecuencia respiratória (f), ventilación por minuto (Ve), tiempo inspiratorio/tiempo total (Ti/Ttot), flujo inspiratorio medio (Vi), presiones bucales máximas: máxima presión inspiratoria (MIP) y máxima presión espiratoria (MEP), presión pleural máxima (Pplmax), presiones transdiafragmáticas durante diferentes maniobras (Pdi) y mediciones de la fuerza y resistencia de los músculos esqueléticos. Tras la administración del lorazepam no se encontraron cambios en la espirometría (FVC, FEV1, ni FEV1/FVC), aunque sí existió una reducción del 20 por ciento en la Ve, debida a una minución en el Vt, que se acompañó de un pequeño pero significativo incremento en la PaCO2. La fuerza y resistencia de los músculos esqueléticos disminuyó significativamente (22 y 50 por ciento respectivamente), al igual que la MIP, MEP, MVV, Ppl y Pdi, que mostraron también reducciones significativas. Se concluye que una dosis única de lorazepam por vía sublingual, a la par que disminuye la ventilación, reduce la fuerza y la resistencia de la musculatura respiratoria en pacientes con EPOC en situación estable.

Efecto agudo del lorazepam sobre los musculos respiratorios en los pacientes con EPOC estable / Acute effect of lorazepam on respiratory muscles in stable patients with chronic obstructive pulmonary disease

Con el objetivo de aclarar los efectos de las benzodiacepinas sobre los músculos respiratorios en pacientes con sobrecarga crónica de los mismos debida a enfermedad pulmonar obstructiva crónica (EPOC), se estudiaron 9 pacientes estables con EPOC avanzado (volumen espiratorio forzado en 1 segundo - FEV 1- 0,91 + 0,31 litros), en quienes, antes y 1 hora después de la administración de lorazepam 1,5 a 2 mg por vía sublingual, se evaluaron la capacidad vital forzada (FVC), FEV 1, ventilación voluntaria máxima (MVV), presión arterial de oxígeno (PaO2), presión arterial de anhídrido carbónico (PaCO2), volumen corriente (Vt), frecuencia respiratória (f), ventilación por minuto (Ve), tiempo inspiratorio/tiempo total (Ti/Ttot), flujo inspiratorio medio (Vi), presiones bucales máximas: máxima presión inspiratoria (MIP) y máxima presión espiratoria (MEP), presión pleural máxima (Pplmax), presiones transdiafragmáticas durante diferentes maniobras (Pdi) y mediciones de la fuerza y resistencia de los músculos esqueléticos. Tras la administración del lorazepam no se encontraron cambios en la espirometría (FVC, FEV1, ni FEV1/FVC), aunque sí existió una reducción del 20 por ciento en la Ve, debida a una minución en el Vt, que se acompañó de un pequeño pero significativo incremento en la PaCO2. La fuerza y resistencia de los músculos esqueléticos disminuyó significativamente (22 y 50 por ciento respectivamente), al igual que la MIP, MEP, MVV, Ppl y Pdi, que mostraron también reducciones significativas. Se concluye que una dosis única de lorazepam por vía sublingual, a la par que disminuye la ventilación, reduce la fuerza y la resistencia de la musculatura respiratoria en pacientes con EPOC en situación estable. (AU)

[Acute effect of lorazepam on respiratory muscles in stable patients with chronic obstructive pulmonary disease]. / Efecto agudo del lorazepam sobre los musculos respiratorios en los pacientes con EPOC estable.

Benzodiazepines are known to cause muscle hypotonia, but their effects on respiratory muscle function, particularly on diaphragm, have not yet been studied. Our aim was to look for any effect of lorazepam on respiratory muscle function in patients with chronic obstructive pulmonary disease (COPD). Nine stable COPD patients (mean +/- SD forced expiratory volume in one second (FEV1) 0.91 +/- 0.31 l) were included in the study. The following measurements were performed before and 1 hour after lorazepam administration (doses: 1.5 to 2 mg) by sublingual route: forced vital capacity (FVC), FEV1, maximal voluntary ventilation (MVV), arterial oxygen tension (PaO2), arterial carbon dioxide tension (PaCO2), minute ventilation (Ve), tidal volume (Vt), respiratory rate (f), inspiratory time/inspiratory plus expiratory time (Ti/Ttot)-, mean inspiratory flow (Vi), maximal inspiratory (MIP) and expiratory (MEP) pressures, maximal pleural pressure (Pplmax), transdiaphragmatic pressures (Pdi) and skeletal muscle strength and endurance. As expected, no change was noted in FVC, FEV1, FEV1/FVC (Table-1). Besides stability of expiratory flows, this denotes no change in collaboration in spite of the sedative effects of lorazepam. There was a 20% decrease in Ve, due to a Vt reduction and a small increase in PaCO2. These could be explained by the central effects of benzodiazepines. Skeletal muscle strength and endurance decreased significantly (22 and 50% respectively-Table 2), in accordance with the previously reported muscular actions of this pharmacological group. Respiratory muscle function parameters, MIP, MEP, MVV and Ppl showed significant reductions (10 to 20 per cent), as was the case with diaphragmatic function measured by Pdi (Muller maneuver with abdominal protrussion and maximal open-glottis expulsive maneuver) (Table 3). This study demonstrates that a single lorazepam dose reduces strength and endurance of respiratory muscle in chronic stable COPD patients.

The stress-induced reduction in monoamine oxidase (MAO) A activity is reversed by benzodiazepines: role of peripheral benzodiazepine receptors.

1. The effect of benzodiazepine pretreatment on the stress-induced decrease in MAO activity in rat tissues using footshock as stress model was investigated. 2. Animals were injected with vehicle, Lorazepam (1.25 mg/kg), or Clonazepam (0.5 mg/kg) 2 hr before or with PK 11195 (0.45 mg/kg) 2.5 hr before being subjected to one session of 10 inescapable footshocks or to a sham session. At the end of the session animals were sacrificed and MAO A and B activities in hearts and brains were determined. 3. Pretreatment of the animals with both Lorazepam and Clonazepam abolished the decrease induced by footshock in MAO A activity in brain. Pretreatment with Lorazepam but not with Clonazepam abolished the stress-induced decrease in MAO A in the heart. Pretreatment with PK 11195 before Lorazepam reversed its effects in the heart but not in the brain. Neither footshock nor any of the drugs used had any effect on heart and brain MAO B. 4. Our results suggest that in the heart but not in the brain, peripheral benzodiazepine receptors play a role in the regulation of MAO A activity under stress conditions.

Lorazepam pharmacodynamics and pharmacokinetics in children.

We evaluated the effects of low doses of lorazepam on episodic versus long-term memory, attention, and somatic and affective symptoms, as well as its pharmacokinetics, in a group of 16 children aged 2.8 to 14.2 years. Psychologic assessments of each child were performed twice before intravenous administration of lorazepam (0.03 mg/kg), and 1 1/2 hours and 24 hours after lorazepam; there were no significant changes in long-term memory, attention, or somatic symptoms. There was a significant decrease in affective symptoms at 1 1/2 hours (p = 0.011), with a trend toward decreased anxiety at 1 1/2 and 24 hours after lorazepam (p = 0.026 and 0.028, respectively). There was also a selective anterograde amnestic effect in 5 of 16 children after lorazepam (p = 0.06). Mean (+/- SD) lorazepam systemic clearance was 1.3 +/- 0.4 ml/min/kg, with a terminal half-life of 10.5 +/- 2.9 hours and an unbound clearance of 15.9 +/- 5.2 ml/min/kg. A group of healthy adult volunteers who were given lorazepam had a mean systemic clearance of 1.0 +/- 0.4 ml/min/kg, somewhat less than that of the children (p = 0.069). There were no significant differences in any lorazepam pharmacokinetic parameter between those children who did versus those who did not have changes in affective symptoms or amnesia. These data should be helpful in establishing the dose of lorazepam in children, as the drug becomes more widely used as an antiemetic, premedicant, and anticonvulsant agent.

Efecto del lorazepam sobre la memoria / Effect of lorazepam on the memory

Las alteraciones en la memoria se han investigado con benzodiazepinas de todas clases, solas o en combinación con otros compuestos, administradas en forma aguda y crónica y por diversas vías, pero utilizando métodos e instrumentos variables, lo que impide comparar los estudios y establecer conclusiones útiles. Los objetivos de este estudio fueron observar qué efecto produce el lorazepam en la memoria inmediata administrado en forma aguda y por vía oral a dosis terapéuticas, y si éste se relaciona con el nivel de sedación producido. Se utilizó el lorazepam por tener una vida media corta y alcanzar niveles sanguíneos máximos a las dos horas. El instrumento utilizado para medir la función mnésica fue la Escala Clínica de Memoria de Wechsler. Se estudiaron 14 voluntarios sanos, masculinos, con edades entre 25 y 30 años, sin antecedentes de uso de psicofármacos. Los resultados permiten establecer las seguientes conclusiones: 1) La Prueba de Memoria de Wechsler es un instrumento útil para la evaluación de las alteraciones mnsica producidas por psicofármacos. 2) El lorazepam produce alteraciones, principalmente en la memoria inmediata a las 2 hrs de administrarlo, lo que coincide con su comportamiento farmacocinético. 3) El tipo de memoria más afectada es la visual. 4) No parece existir relación entre el grado de sedación y las alteraciones de memoria. Hasta el momento no se tienen los conocimientos necesarios para explicar, desde el punto de vista neuroquímico, el efecto amnésico de las benzodiazepinas. Se ha propuesto que pudiera ser secundario a modificaciones de los sistemas colinérgico o vasopresinérgico centrales