Treatment of cannabis dependence using escitalopram in combination with cognitive-behavior therapy: a double-blind placebo-controlled study.

BACKGROUND: Cannabis is the most frequently used illegal substance in the United States and Europe. There is a dramatic increase in the demand for treatment for cannabis dependence. Cannabis users frequently have co-morbid mood symptoms, especially depression and anxiety, and regular cannabis users may self-medicate for such symptoms. OBJECTIVES: We report a double-blind, placebo-controlled treatment study, for the prevention of cannabis use in cannabis-dependent individuals. METHOD: Regular cannabis-dependent users (n = 52) were treated for 9 weeks with weekly cognitive-behavior and motivation-enhancement therapy sessions together with escitalopram 10 mg/day. Urine samples were collected to monitor delta-9 tetrahydrocannabinol (THC) during treatment and questionnaires were administered to assess anxiety and depression. RESULTS: We observed a high rate of dropout (50%) during the 9-week treatment program. Fifty-two patients were included in the intention-to-treat analysis. Of these, ten (19%) remained abstinent after 9 weeks of treatment as indicated by negative urine samples for THC. Escitalopram provided no advantage over placebo in either abstinence rates from cannabis or anxiety and depression scores during the withdrawal and abstinent periods. CONCLUSIONS: Escitalopram treatment does not provide an additional benefit either for achieving abstinence, or for the treatment of the cannabis withdrawal syndrome. Due to limitations of our study, namely, a high dropout rate and effects of low abstinence rates on measures of anxiety, depression and withdrawal, it is premature to conclude that selective serotonin reuptake inhibitors are not effective for treatment of the cannabis withdrawal syndrome.

Severe hyperosmolarity and hypernatremia in an adipsic young woman.

BACKGROUND: Combined deficits in arginine vasopressin secretion (AVP) and thirst sensation can result in life threatening hyperosmolality and hypernatremia. Complications include seizures, profound volume contraction and renal failure. Fortunately, this is an uncommon clinical condition, with approximately 70 cases reported in the literature over the past 47 years [1]. Defects in AVP secretion and/or synthesis produce central diabetes insipidus (DI), polyuria with polydipsia, hypernatremia and hyperosmolality. Most awake and alert patients with an intact thirst stimulus will "drink" themselves back to a normal serum sodium and osmolality. However, if there is concomitant destruction of the osmoreceptors that regulate thirst, osmolal and volume homeostasis cannot be maintained. The relationships between urine osmolarity and serum osmolarity and plasma vasopressin levels are vital for distinguishing a reset osmostat from central DI. METHODS: After obtaining approval from our institutional review board, we retrospectively reviewed the medical record of a 37-year-old patient who presented to our institution with a serum sodium of 176 mEq/l. RESULTS: Admission laboratory examination revealed: hemoglobin 12.8 g/dl; white blood cell count 4.7 × 103/µl, with a normal differential; random serum glucose 91 mg/dl ; sodium 176 mEq/l; plasma osmolality 366 mOsm/kg; BUN 33 mg/dl; serum creatinine 1 mg/dl; calcium 9.5 mg/dl; urine specific gravity 1.032; and urine osmolality 1,172 mOsm/kg. An MRI with contrast of the sella/ pituitary revealed an enhancing mass centered within the suprasellar cistern and anterior third ventricle, measuring 3.0 × 3.9 × 3.4 cm. The lesion appeared to involve the hypothalamus and displaced the optic chiasm inferiorly. Evaluation of pituitary function revealed normal serum levels of thyroid stimulating hormone, AM cortisol, luteinizing hormone, follicle stimulating hormone and prolactin. Figure 1 illustrates the relationship between measured serum AVP levels and serum osmolality. Figure 2 shows the relationship between measured urine and serum osmolality. If the serum AVP levels were not available, it would appear as though the patient had a reset osmostat. The kidneys appear to appropriately generate maximally concentrated urine at a serum osmolality above 348 but are unable to below this value. CONCLUSIONS: When compared with the normal curve, our patient's AVP levels were lower than expected for the corresponding osmolality. This pattern is consistent with a partial central DI. She does not have a reset osmostat. In the presence of significant volume contraction and a reduced GFR, her kidneys produced more concentrated urine despite markedly decreased central vasopressin production. As the volume contraction abated and the GFR improved, polyuria recurred, despite persistent hyperosmolarity and hypernatremia.

Pharmacological treatment of cannabis dependence.

Cannabis is the most frequently used illegal psychoactive substance in the world. There is a significant increase in the number of treatment admissions for cannabis use disorders in the past few years, and the majority of cannabis-dependent individuals who enter treatment have difficulty in achieving and maintaining abstinence. Thus, there is increased need for medications that can be used to treat this population. So far, no medication has been shown broadly and consistently effective; none has been approved by any national regulatory authority. Medications studied have included those that alleviate symptoms of cannabis withdrawal (e.g., dysphoric mood, irritability),those that directly affect endogenous cannabinoid receptor function, and those that have shown efficacy in treatment of other drugs of abuse or psychiatric conditions. Buspirone is the only medication to date that has shown efficacy for cannabis dependence in a controlled clinical trial. Results from controlled human laboratory studies and small open-label clinical trials suggest that dronabinol, the COMT inhibitor entacapone, and lithium may warrant further study. Recent pre-clinical studies suggest the potential of fatty acid amide hydrolase (FAAH) inhibitors such as URB597, endocannabinoid-metabolizing enzymes, and nicotinic alpha 7 receptor antagonists such as methyllycaconitine (MLA).Controlled clinical trials are needed to evaluate the clinical efficacy of these medications and to validate the laboratory models being used to study candidate medications.

A mathematical model of rat cortical collecting duct: determinants of the transtubular potassium gradient.

In assessing disorders of potassium excretion, urine composition is used to calculate the transtubular gradient (TTKG), as an estimate of tubule fluid concentration, at a point when the fluid was last isotonic to plasma, namely, within the cortical collecting duct (CCD). A mathematical model of the CCD has been developed, consisting of principal cells and alpha- and beta-intercalated cells, and which includes Na(+), K(+), Cl(-), HCO, CO(2), H(2)CO(3), phosphate, ammonia, and urea. Parameters have been selected to achieve fluxes and permeabilities compatible with data obtained from perfusion studies of rat CCD under the influence of both antidiuretic hormone and mineralocorticoid. Both epithelial (flat sheet) and tubule models have been configured, and model calculations have focused on the determinants of the TTKG. Using the epithelial model, luminal K(+) concentrations can be computed at which K(+) secretion ceases (0-flux equilibrium), and this luminal concentration derives from the magnitude of principal cell peritubular uptake of K(+) via the Na-K-ATPase, relative to principal cell peritubular membrane K(+) permeability. When the model is configured as a tubule and examined in the context of conditions in vivo, osmotic equilibration of luminal fluid produces a doubling of the initial K(+) concentration, which, depending on delivered load, may be substantially greater than the zero-flux equilibrium value. Under such circumstances, the CCD will be a site for K(+) reabsorption, although the relatively low permeability ensures that this reabsorptive flux is likely to be small. Osmotic equilibration may also raise luminal NH(3) concentrations well above those in cortical blood. In this situation, diffusive reabsorption of NH(3) provides a mechanism for base reclamation without the metabolic cost of active proton secretion.

The processing of automatic thoughts of drug use and craving in opiate-dependent individuals.

This study investigated the processing of sentences describing craving and withdrawal in opiate-dependent individuals. Eighteen patients who attended a methadone maintenance clinic for obtaining methadone, 18 patients who were not treated with methadone, and 18 control family members performed on a computerized contextual priming task. The task was priming sentences (craving, withdrawal, or neutral) to words (addiction, neutral, or nonwords). The methadone group was slower to process all sentences compared with family members. They were also faster to process drug-related words following withdrawal-related sentences compared with neutral words following neutral sentences. Finally, they were slower to recognize neutral words following neutral sentences compared with the nonmethadone group. Results suggest that the processing of information describing withdrawal and craving for drugs plays an important role in opiate dependence.

A hydrodynamic mechanosensory hypothesis for brush border microvilli.

In the proximal tubule of the kidney, Na(+) and HCO(3)(-) reabsorption vary proportionally with changes in axial flow rate. This feature is a critical component of glomerulotubular balance, but the basic mechanism by which the tubule epithelial cells sense axial flow remains unexplained. We propose that the microvilli, which constitute the brush border, are physically suitable to act as a mechanosensor of fluid flow. To examine this hypothesis quantitatively, we have developed an elastohydrodynamic model to predict the forces and torques along each microvillus and its resulting elastic bending deformation. This model indicates that: 1) the spacing of the microvilli is so dense that there is virtually no axial velocity within the brush border and that drag forces on the microvilli are at least 200 times greater than the shear force on the cell's apical membrane at the base of the microvilli; 2) of the total drag on a 2.5-microm microvillus, 74% appears within 0.2 microm from the tip; and 3) assuming that the structural strength of the microvillus derives from its axial actin filaments, then a luminal fluid flow of 30 nl/min produces a deflection of the microvillus tip which varies from about 1 to 5% of its 90-nm diameter, depending on the microvilli length. The microvilli thus appear as a set of stiff bristles, in a configuration in which changes in drag will produce maximal torque.

A mathematical model of the outer medullary collecting duct of the rat.

A mathematical model of the outer medullary collecting duct (OMCD) has been developed, consisting of alpha-intercalated cells and a paracellular pathway, and which includes Na(+), K(+), Cl(-), HCO(3)(-), CO(2), H(2)CO(3), phosphate, ammonia, and urea. Proton secretion across the luminal cell membrane is mediated by both H(+)-ATPase and H-K-ATPase, with fluxes through the H-K-ATPase given by a previously developed kinetic model (Weinstein AM. Am J Physiol Renal Physiol 274: F856-F867, 1998). The flux across each ATPase is substantial, and variation in abundance of either pump can be used to control OMCD proton secretion. In comparison with the H(+)-ATPase, flux through the H-K-ATPase is relatively insensitive to changes in lumen pH, so as luminal acidification proceeds, proton secretion shifts toward this pathway. Peritubular HCO(3)(-) exit is via a conductive pathway and via the Cl(-)/HCO(3)(-) exchanger, AE1. To represent AE1, a kinetic model has been developed based on transport studies obtained at 38 degrees C in red blood cells. (Gasbjerg PK, Knauf PA, and Brahm J. J Gen Physiol 108: 565-575, 1996; Knauf PA, Gasbjerg PK, and Brahm J. J Gen Physiol 108: 577-589, 1996). Model calculations indicate that if all of the chloride entry via AE1 recycles across a peritubular chloride channel and if this channel is anything other than highly selective for chloride, then it should conduct a substantial fraction of the bicarbonate exit. Since both luminal membrane proton pumps are sensitive to small changes in cytosolic pH, variation in density of either AE1 or peritubular anion conductance can modulate OMCD proton secretory rate. With respect to the OMCD in situ, available buffer is predicted to be abundant, including delivered HCO(3)(-) and HPO(4)(2-), as well as peritubular NH(3). Thus, buffer availability is unlikely to exert a regulatory role in total proton secretion by this tubule segment.

Quantitative IgE antibody assays in allergic diseases.

During the past several years, immunoassays for specific IgE antibodies have been refined to permit reporting results in mass units. Thus quantitative immunoassays for IgE antibodies may be an adjunct to skin tests. In cases of food allergy among children with atopic dermatitis, cutoff values for IgE antibody concentrations to egg, milk, peanut, and fish have been derived to provide 95% positive and 90% negative predictive values. Food-specific IgE antibody determinations can also be used to predict which food allergies are resolving spontaneously. Elevated egg-specific IgE antibody levels in infancy are associated with significantly increased risk for development of inhalant allergies later in childhood. In cases of inhalant allergy, specific IgE antibody levels correlate closely with results of inhalation challenge studies in cat-sensitive persons. Also, mite-specific IgE antibody levels correlate significantly with the mite allergen contents of reservoir dust in the homes of mite-sensitive persons. Immunoassays for quantitation of specific IgE antibodies may be used to document allergen sensitization over time and to evaluate the risk of reaction on allergen exposure. However, immunoassays and skin tests are not entirely interchangeable, and neither will replace the other in appropriate circumstances.

Modeling epithelial cell homeostasis: steady-state analysis.

Critical to epithelial cell viability is the homeostasis of cell volume and composition during changes in transcellular transport. In this study, two previously developed mathematical models (principal cell of the collecting duct and proximal tubule cell) are approximated by their linearizations about a reference condition. This yields matrices which estimate cell volume, cell composition, and transcellular fluxes in response to perturbations of bath conditions and membrane transporter activity. These approximations are themselves extended with the inclusion of linear dependence of membrane transport coefficients on cell variables (e.g., volume, solute concentrations, or electrical potential). This provides cell models with variable permeabilities, which may be homeostatic, and which can be examined systematically: sequentially testing each membrane permeability and its controlling cell variable. In the proximal tubule approximation, volume-mediated increases in peritubular K-Cl or Na-3HCO3 cotransport, and volume-mediated decreases in Na,K-ATPase activity are homeostatic; modulation of peritubular K permeability has little impact. In the principal cell model, volume homeostasis is afforded by volume-sensitive peritubular Na/H exchange or Cl- conductance. Predictions from the linear analysis are confirmed in the full models. This approach yields a systematic examination of homeostasis in an epithelial model, and identifies candidate control parameters.

Insights from mathematical modeling of renal tubular function.

Mathematical models of proximal tubule have been developed which represent the important solute species within the constraints of known cytosolic concentrations, transport fluxes, and overall epithelial permeabilities. In general, model simulations have been used to assess the quantitative feasibility of what appear to be qualitatively plausible mechanisms, or alternatively, to identify incomplete rationalization of experimental observations. The examples considered include: (1) proximal water reabsorption, for which the lateral interspace is a locus for solute-solvent coupling; (2) ammonia secretion, for which the issue is prioritizing driving forces - transport on the Na+/H+ exchanger, on the Na,K-ATPase, or ammoniagenesis; (3) formate-stimulated NaCl reabsorption, for which simple addition of a luminal membrane chloride/formate exchanger fails to represent experimental observation, and (4) balancing luminal entry and peritubular exit, in which ATP-dependent peritubular K+ channels have been implicated, but appear unable to account for the bulk of proximal tubule cell volume homeostasis.

A mathematical model of the inner medullary collecting duct of the rat: pathways for Na and K transport.

A mathematical model of the inner medullary collecting duct (IMCD) of the rat has been developed representing Na+, K+, Cl-, HCO3-, CO2, H2CO3, phosphate, ammonia, and urea. Novel model features include: finite rates of hydration of CO2, a kinetic representation of the H-K-ATPase within the luminal cell membrane, cellular osmolytes that are regulated in defense of cell volume, and the repeated coalescing of IMCD tubule segments to yield the ducts of Bellini. Model transport is such that when entering Na+ is 4% of filtered Na+, approximately 75% of this load is reabsorbed. This requirement renders the area-specific transport rate for Na+ comparable to that for proximal tubule. With respect to the luminal membrane, there is experimental evidence for both NaCl cotransport and an Na+ channel in parallel. The experimental constraints that transepithelial potential difference is small and that the fractional apical resistance is greater than 85% mandate that more than 75% of luminal Na+ entry be electrically silent. When Na+ delivery is limited, an NaCl cotransporter can be effective at reducing luminal Na+ concentration to the observed low urinary values. Given the rate of transcellular Na+ reabsorption, there is necessarily a high rate of peritubular K+ recycling; also, given the lower bound on luminal membrane Cl- reabsorption, substantial peritubular Cl- flux must be present. Thus, if realistic limits on cell membrane electrical resistance are observed, then this model predicts a requirement for peritubular electroneutral KCl exit.

A mathematical model of the inner medullary collecting duct of the rat: acid/base transport.

A mathematical model of the inner medullary collecting duct (IMCD) of the rat has been developed that is suitable for simulating luminal buffer titration and ammonia secretion by this nephron segment. Luminal proton secretion has been assigned to an H-K-ATPase, which has been represented by adapting the kinetic model of the gastric enzyme by Brzezinski et al. (P. Brzezinski, B. G. Malmstrom, P. Lorentzon, and B. Wallmark. Biochim. Biophys. Acta 942: 215-219, 1988). In shifting to a 2 H+:1 ATP stoichiometry, the model enzyme can acidify the tubule lumen approximately 3 pH units below that of the cytosol, when luminal K+ is in abundance. Peritubular base exit is a combination of ammonia recycling and HCO3- flux (either via Cl-/HCO3- exchange or via a Cl- channel). Ammonia recycling involves NH4(+) uptake on the Na-K-ATPase followed by diffusive NH3 exit [S. M. Wall. Am. J. Physiol. 270 (Renal Physiol. 39): F432-F439, 1996]; model calculations suggest that this is the principal mode of base exit. By virtue of this mechanism, the model also suggests that realistic elevations in peritubular K+ concentration will compromise IMCD acid secretion. Although ammonia recycling is insensitive to carbonic anhydrase (CA) inhibition, the base exit linked to HCO3- flux provides a CA-sensitive component to acid secretion. In model simulations, it is observed that increased luminal NaCl entry increases ammonia cycling but decreases peritubular Cl-/HCO3- exchange (due to increased cell Cl-). This parallel system of peritubular base exit stabilizes acid secretion in the face of variable Na+ reabsorption.

Water does not flow across the tight junctions of MDCK cell epithelium.

Although it has been known for decades that the tight junctions of fluid-transporting epithelia are leaky to ions, it has not been possible to determine directly whether significant transjunctional water movement also occurs. An optical microscopic technique was developed for the direct visualization of the flow velocity profiles within the lateral intercellular spaces of a fluid-absorptive, cultured renal epithelium (MDCK) and used to determine the velocity of the fluid flow across the tight junction. The flow velocity within the lateral intercellular spaces fell to near zero adjacent to the tight junction, showing that significant transjunctional flow did not occur, even when transepithelial fluid movement was augmented by imposition of osmotic gradients.

Dynamics of cellular homeostasis: recovery time for a perturbation from equilibrium.

In the collecting duct in vivo, the principal cell encounters a wide range in luminal flow rate and luminal concentration of NaCl. As a consequence, there are substantial variations in the transcellular fluxes of Na+ and Cl-, conditions which would be expected to perturb cell volume and cytosolic concentrations. Several control mechanisms have been identified which can potentially blunt these perturbations, and these entail cellular regulation of the luminal membrane Na+ channel and peritubular membrane K+ and Cl- channels. To illustrate the impact of these regulated channels, a mathematical model of the principal cell of the rat cortical collecting duct has been developed, in which ion channel permeabilities are either constant or regulated. In comparison to the model with fixed permeabilities, the model with regulated channels demonstrates enhanced cellular homeostasis following steady-state variation in luminal NaCl. However, in the transient response to a cytosolic perturbation, the difference in recovery time between the models is small. An approximate analysis is presented which casts these models as dynamical systems with constant coefficients. Despite the presence of regulated ion channels, concordance of each model with its linear approximation is verified for experimentally meaningful perturbations from the reference condition. Solution of a Lyapunov equation for each linear system yields a matrix whose application to a perturbation permits explicit estimation of the time to recovery. Comparison of these solution matrices for regulated and non-regulated cells confirms the similarity of the dynamic response of the two models. These calculations suggest that enhanced homeostasis by regulated channels may be protective, without necessarily hastening recovery from cellular perturbations.

Coupling of entry to exit by peritubular K+ permeability in a mathematical model of rat proximal tubule.

In the proximal tubule in vivo, glomerulotubular balance requires that tubule epithelial cells accommodate a twofold variation in Na+ reabsorption through the Na+/H+ exchanger of the luminal membrane. In a mathematical model of proximal tubule, in which permeability coefficients are fixed, doubling flux through the Na+/H+ antiporter produces a substantial increase in cell volume and cytosolic HCO3-. In this model, it is possible to vary peritubular K+ permeability with changes in luminal Na+ entry, so that cell volume is constrained to be constant. In these calculations, the model predicts that peritubular hyperpolarization and nearly constant cytosolic HCO3- will accompany increases in luminal Na+ entry. Realistic models of variable peritubular K+ permeability might include a functional dependence on flux through the Na(+)-K(+)-adenosinetriphosphatase, cytosolic pH, or cell volume. When K+ permeability is represented as a function of any of these variables, homeostatic control of cell volume and pH can be obtained over a physiological variation of Na+/H+ flux. However, when luminal Na+ entry is via Na(+)-glucose cotransport, volume homeostasis is best when peritubular K+ permeability depends on the rate of active Na+ transport. For any modulator of K+ permeability, realistic constraints on the value of this parameter suggest that peritubular K+ permeability is, by itself, not sufficient to maintain cell volume within narrow limits. Parallel activation of another exit pathway, such as peritubular Na(+)-3 HCO3- cotransport, may be required to achieve the necessary homeostasis.

Acid/base transport in a model of the proximal tubule brush border: impact of carbonic anhydrase.

A mathematical model of the brush border of the proximal tubule (T. A. Krahn, P. S. Aronson, and A. M. Weinstein. Bull. Math. Biol, 56: 459-490, 1994) has been extended by the inclusion of CO2 and H2CO3 as diffusible species and by the inclusion of finite rate constants for the hydration of CO2. This permits the simulation of carbonic anhydrase (CA) activity and its inhibition. We confirm the result of our previous study, which is that, in the presence of CA, the unstirred layer has only a modest effect on the observed formic acid permeability. CA inhibition results in disequilibrium pH gradients, and the effect of these gradients on formic acid permeability depends on the presence of other membrane transport proteins. We also examined the impact of CA activity on the flux of total CO2 through the brush border. Under physiological conditions, CA inhibition depressed NaHCO3 reabsorption through the brush border by interfering with the HCO3(-)-facilitated diffusion of CO2. However, the determination of brush-border CO2 permeability, using an imposed CO2 gradient, was relatively uninfluenced by CA activity. Finally, we inserted a kinetic representation of the Na+/H+ exchanger into the brush-border model. Even when luminal and cytosolic diffusion coefficients were increased 1,000-fold, there was no effect on brush-border Na+ flux. This suggests that variations in the unstirred layer cannot be responsible for the flow dependence of Na+ reabsorption.

Cognitive processing in post-traumatic stress disorder.

Recent research has suggested an abnormal attentional bias to threat in anxiety disorders. We have assessed the processing of thoughts of trauma, panic attacks, general fear and positive affect in a cohort of 15 war veterans with post-traumatic stress disorder (PTSD) and an age- and sex-matched normal control group. Subjects with PTSD showed delayed processing of self-referential sentences when the themes of the sentences were traumatic experiences or positive affect, compared with controls. However, they were more efficient than control subjects in the processing of sentences describing situations of panic attacks and general fear. It would therefore appear that in patients with PTSD, cognitive processing is hindered by personally relevant themes of past traumatic experiences, whereas it may be facilitated by information related to general threat or internal body sensations of panic.

Visual ERPs evidence for enhanced processing of threatening information in anxious university students.

There is accumulating evidence that highly anxious individuals selectively attend to threatening information; however, contrary to expectations, there is no evidence of enhanced processing of threat stimuli in those individuals. We investigated this question by using a sample of 20 University students who were split into two groups consisting of 10 high-anxious and 10 low-anxious subjects according to Spielberger Trait Anxiety Inventory score (median STAI = 40). Without emphasizing speed, subjects were required to decide whether visually presented words (positive, neutral, or threat) matched semantically with previous priming sentences (threat or positive) displayed on a computer screen (altogether, two types of priming sentences and three types of probe words). There was a fixed interval of 1.1 seconds between priming sentences (SI) and probe words (S2) as well as between each priming sentence word. Response time and visual event-related potentials (ERPs) were recorded in both conditions. The results showed that, compared to the Low-Anxious group, the amplitude of N100 and P400 were enhanced for the High-Anxious group in the threat priming conditions. Low-anxious individuals showed almost identical processing of threat-related situations and positive situations. Furthermore, the P400 peak latency was shorter for emotional incongruous probes in high-anxious individuals. ERPs results of the experiment suggest that highly anxious individuals deploy more processing resources to threatening information. This bias in information processing occurs in the absence of any behavioral changes (indicated by reaction times). Attentional bias in anxiety therefore implies that threatening information is given a priority over other information and is more persistently activated in anxiety states.