Kegg Pathway: Anxiolytics

Prog Neuropsychopharmacol Biol Psychiatry. 2008 Aug 7;
McDermott C, Kelly JP

The use of animal models (particularly rats) in research for developing drugs for central nervous system diseases is well validated. However a range of strains are often utilised in these models. The Lister-Hooded (LH) strain is beginning to be increasingly used in preclinical investigations. Thus, the objective of the present study was to investigate the comparative behavioural pharmacology of this strain, with the two most widely used rat strains, namely the Sprague-Dawley (SD), and Wistar (W) strains. The tests used were the forced swim test (FST) for antidepressants, the amphetamine-locomotor activity test for antipsychotics, the elevated plus maze (EPM) for Anxiolytics, as well as tests of general locomotor activity using home cage monitoring (HCM) and the open field test. Continuous HCM revealed a significantly higher daily activity and lower nocturnal activity for LH compared to the other strains; there were no strain-related differences in the open field test. In the FST, there were no strain differences in immobility time and a similar magnitude of desipramine-induced reduction in immobility across strains. In the locomotor activity test, control LH rats showed significantly higher activity whilst significant amphetamine-induced hyperactivity was seen only with the LH and W strains. In the EPM, control LH rats had a significantly larger percentage of open arm entries, whilst only the SD strain displayed a significant diazepam-induced increase in this parameter. These findings suggest that strain variation can cause markedly different results in behavioural pharmacological tests where locomotor activity plays a significant role, and should be taken into account when selecting a strain for evaluating the behavioural effects of psychotropic drugs. Such differences in locomotor activity in the LH strain could be accounted for by an altered diurnal pattern in this strain.

Neuropharmacology. 2008 Aug 5;
Wang F, Xu Z, Ren L, Tsang SY, Xue H

Baicalin, a naturally occurring flavonoid, was previously reported to induce anxiolytic-like effect devoid of sedation and myorelaxation in mice, acting through type A gamma-aminobutyric acid (GABA(A)) receptor benzodiazepine (BZ) site. The present study further expanded the behavioral pharmacology profile of baicalin and subtype selectivity was explored as a possible mechanism underlying its in vivo effects on mice. Baicalin was characterized using convulsion, memory, and motor function related animal tests; and its selectivity towards recombinant GABA(A) receptor subtypes expressed in HEK 293T cells was determined by radioligand binding assay and electrophysiological studies. In the picrotoxin-induced seizure, step-through passive avoidance and rotarod tests, the anticonvulsant, amnesic and motor incoordination effects commonly associated with classical BZs were not observed when baicalin was administered at effective anxiolytic doses, demonstrating a separation of the anticonvulsant, amnesic and motor incoordination effects from the anxiolytic-like effect. Although baicalin exhibited higher binding affinity for the alpha(1)-containing GABA(A) subtype compared with alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes, this was not statistically significant. In contrast to the classical BZ diazepam, baicalin showed significant preference for alpha(2)- and alpha(3)-containing subtypes compared to alpha(1)- and alpha(5)-containing subtypes in whole-cell patch clamp studies (P<0.01). Its subtype selectivity suggested that baicalin exerted its in vivo anxiolytic-like effect mainly through the alpha(2)- and alpha(3)-containing subtypes. Therefore, the present study revealed an underlying mechanism for the selective anxiolytic profile of baicalin, suggesting alpha(2)- and alpha(3)-containing subtypes were important drug targets for flavonoid-based Anxiolytics.

Rev Assoc Med Bras. 2008 Jul-Aug; 54(4): 353-6
Gorzoni ML, Fabbri RM, Pires SL

BACKGROUND: Determine, according to the Beer-Fick criteria, the prevalence of drugs potentially inappropriate for the elderly available as generic medication in Brazil. METHODS: Analysis of the list of generic medications issued by " Diário Oficial da União" on July/12/2004 and of the page of the National Agency for Sanitary Surveillance (ANVISA) - www.anvisa.gov.br, using the Beers-Fick criteria. RESULTS: From the list of 299 products 20 (6.7% of the total) included in the Beers-Fick criteria were analyzed, mainly in the categories of Anxiolytics, platelet antiaggregants, antiallergics, anti-angina and vasodilators, antiarrythmics, antidepressants, antispasmodics, anti-hypertensive's, non steroid antinflammatories, antiulceratives and cardiac glycosides. These criteria do not include drugs such as cough suppressants, cinnarizine, diltiazem, piracetam, quinolones, xanthines, creams, ointments and ophthalmic solutions which are also present in the list of generic medication. CONCLUSION: The Beers-Fick criteria may prevent use of drugs potentially inappropriate for the elderly, however, it should be stressed that these criteria are not complete for Brazilian generic medications.

Lakartidningen. 2008 Jul 9-22; 105(28-29): 2026

Acta Med Croatica. 2008 May; 62(2): 205-10
Trkanjec Z, Aleksić-Shihabi A

Tension-type headache is one of the most common and most significant primary headaches. Tension-type headache is a very heterogeneous disorder. It can be divided into episodic and chronic tension-type headache. The pain is a dull, pressing, tightening, typically band-like sensation. The pain is of non-pulsating quality, the location is bilateral, and there is no nausea, vomiting, phonophobia or photophobia. There are no prodromal symptoms or aura. The pain is mild to moderate and it does not aggravate with routine physical activities. Some patients have increased tenderness of pericranial muscles. Psychological factors are common in tension-type headache. Nitric oxide has an important role in the pathophysiology of chronic tension-type headache. Probably it promotes central sensitization and therefore increases nociception. In differential diagnosis of tension type-headache, all structural and metabolic diseases causing headache have to be ruled out, as well as all other primary headaches. All comorbid and coexistent states should also be considered. In the treatment of tension-type headache, pharmacological and non-pharmacological methods are employed. Analgesics, myorelaxants, Anxiolytics and antidepressants are most commonly used, as well as physical therapy, massage, acupuncture, behavioral therapy and psychotherapy. Recently, the applications of botulinum toxin and acupuncture have been described in the treatment and prophylaxis of tension-type headache.

J Indian Med Assoc. 2008 Feb; 106(2): 124-5
Pandey CK, Singh N, Singh PK

Trigeminal neuralgia is sudden, usually unilateral, severe, stabbing, brief recurrent pain in the distribution area of one or more of the branches of trigeminal nerve. Various pharmacological agents including carbamazepine, oxcarbazepine, phenytoin, lamotrigine, baclofen and clonazepam have been tried with variable success rate. Here a case of idiopathic trigeminal neuralgia is presented. The patient presented in the emergency room with severe pain in the distribution area of maxillary branch of trigeminal nerve, resistant to conventional pharmacotherapy, managed successfully with gabapentin without untoward side-effects.

Anaesthesia. 2008 Aug; 63(8): 887
Zanette G, Facco E, Manani G

Indian J Exp Biol. 2008 Jun; 46(6): 470-5
Gupta GL, Rana AC

Withania somnifera (WS) or its psychotropic preparation is known to play a critical role in morphine, alcohol and benzodiazepines addiction. This study investigates the role of WS in acute ethanol and withdrawal from chronic ethanol consumption using elevated plus maze paradigm in rats. Acute administration of ethanol (1.5-2 g/kg, ip) triggered anxiolytic effect and withdrawal from prolonged ethanol (9% v/v ethanol, 15 days) consumption elicited enhanced behavioral despair (anxiety). Acute administration of WS (50 mg/kg, oral) potentiated the anxiolytic action of subeffective dose of ethanol (0.5 or 1 g/kg, ip). Moreover, the ethanol withdrawal anxiety was markedly antagonized in dose dependent manner by WS at 200 and 500 mg/kg or higher dose of ethanol (2.5 g/kg). However, co-administration of subeffective doses of WS (50 mg/kg, oral) and ethanol also attenuated withdrawal-induced anxiety due to chronic ethanol (9% v/v ethanol, 15 days) consumption. The results suggest the protective effect of WS in the management of ethanol withdrawal reactions.

Curr Top Med Chem. 2008; 8(12): 1024-34
Lacivita E, Leopoldo M, Berardi F, Perrone R

The serotonin receptor subtype 5 HT(1A) was one of the first serotonin receptor subtypes pharmacologically characterized. Over the last twenty years the 5 HT(1A) receptor has been the object of intense research efforts as witnessed by the 5 HT(1A) acting drugs marketed as Anxiolytics. In recent years, several new chemical entities targeting the 5 HT(1A) receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic indications (neuroprotection, cognitive impairment, Parkinson Disease and related disorders, pain treatment). The present review will focus on those 5 HT(1A) receptor agents that entered preclinical trials starting from 2000.

Curr Top Med Chem. 2008; 8(12): 1008-23
Dawson LA, Bromidge SM

Since the initial observations linking 5-HT to psychiatric illness, evidence for a role of 5-HT and, in particular, a decreased brain serotonergic function in the pathology of a plethora of related disorders, has grown. However, it is the role of 5-HT in the pathogenesis of anxiety disorders and depression and the mechanism of action of antidepressants which has received the most attention. Thus enhanced serotonergic neurotransmission has become one of the unifying mechanisms of action of modern day antidepressants/Anxiolytics such as monoamine oxidase inhibitors, tricyclic antidepressants, and serotonin reuptake inhibitors. Interestingly all of these treatments are associated with a delay to therapeutic efficacy and in some cases treatment resistance, despite immediate enhancements in serotonergic neurotransmission. The postulated reason for this is the need for temporal neuroplastic changes in the control of serotonergic neurotransmission, and more specifically changes in 5-HT(1) autoreceptor function. Thus significant research has gone into pharmacologically targeting these 5-HT(1) autoreceptors as a means of augmenting the efficacy of current therapeutic mechanisms. Here we will review the rationale behind the various augmentation strategies adopted and the progress made in identifying novel therapeutics for conditions such as depression and anxiety disorders.

Curr Drug Saf. 2008 Sep; 3(3): 185-9
Vestergaard P

Many central nervous system active drugs can alter postural balance, increasing the risk of fractures. Anxiolytics and sedatives include the benzodiazepines, and these have been associated with a limited increase in the risk of fractures, even at low doses, probably from an increased risk of falls. No systematic differences have been shown between benzodiazepines with long and short half-lives. Although the increase in risk of fractures was limited, care must still be taken when prescribing for older fall-prone subjects at risk of osteoporosis. Neuroleptics may be associated with a decrease in bone mineral density and a very limited increase in fracture risk. Antidepressants are associated with a dose-dependent increase in the risk of fractures. The increase in relative risk of fractures seems to be larger with selective serotonin reuptake inhibitors (SSRIs) than with tricyclic antidepressants. The reason for this is not known but may be linked to serotonin effects on bone cells and the risk of falls. With the wide use of SSRIs, more research is needed. Lithium is associated with a decrease in the risk of fractures. This may be linked to its effects on the Wnt glycoprotein family, which is a specialised signalling system for certain cell types.

Osteoporos Int. 2008 Aug 9;
Abrahamsen B, Brixen K

A nationwide case-control study was performed in 62,865 men aged 50+ using fracture data from the national hospital discharge register to screen all redeemed prescriptions in the past 5 years for significant mapping to fracture risk, employing measures to control for false discovery rate. INTRODUCTION: Osteoporosis in men is frequently related to alcohol abuse, hypogonadism, hypercalciuria, or the use of glucocorticoids. Very limited information is available on the impact of other medications on fracture risk in men. METHODS: We conducted a nationwide population-based case-control study collecting fracture data from the Danish National Hospital Discharge Register and prescriptions from the National Prescriptions Database (1995-2000). We included men aged 50+ years, with hospital-treated fractures in the year 2000 (n = 15,716), and age- and sex-matched controls (n = 47,149). RESULTS: We identified 3.2 million redemptions of prescriptions for 1,073 different drugs. The analysis confirmed associations between fracture risk and use of sedatives, anti-epileptics, anti-psychotics, Anxiolytics, SSRI, opioids and other analgesics, loop diuretics, and glucorticoids. New associations were also found. We observed an odds ratio (OR [95% CI] for any fracture) for fracture in users of dopaminergic agents (1.6 [1.3-1.9]) and iron compounds (1.2 [1.1-1.5]). The largest impact on fracture risk at population level was exerted by loop diuretics and analgesics. CONCLUSIONS: An array of drugs is associated with fracture risk in men. The "prescriptiome" analysis can be used as a surveillance tool for drug-induced osteoporosis and in the planning of preventive measures.

J Fam Pract. 2007 Mar; 56(3 Suppl Diagnosis): S20-1
Apgar BS

J Fam Pract. 2007 Mar; 56(3 Suppl Diagnosis): S16-7
Levy BS

Arzneimittelforschung. 2008; 58(6): 269-76
Lim LW, Temel Y, Visser-Vandewalle V, Steinbusch H, Schruers K, Hameleers R, Esquivel G, Griez E, Blokland A

INTRODUCTION: Buspirone (CAS 33386-08-2) is reported to have anxiolytic effects in humans and is mostly described for mild anxiety. To further explore the effects of buspirone on different levels of anxiety, the effect of buspirone was evaluated in two different conditions of the open field which were distinguished as low and high anxiety (enclosed and exposed open field, respectively). MATERIALS AND METHODS: Twenty-eight albino Wistar rats (350-400 g) were tested in two different arena settings, an enclosed and an exposed open field. Fourteen animals were initially injected with 1 ml saline while the others (n = 14) received buspirone 3 mg/kg. RESULTS: The data showed clear differences in the two open-field settings, suggesting a higher anxiety level in the exposed open field. In addition, correlation analysis showed that the two anxiety tests measure different aspects of anxiety. Buspirone treatment reduced the behavioral activity in both the enclosed and exposed open-field, which is generally interpreted as an anxiogenic effect. However, buspirone increased the time in the center areas and decreased the frequencies in the outer regions. These behavioral changes are generally seen as an anxiolytic effect. Correlation analysis showed that buspirone treatment disrupted the relation between indices of anxiety. CONCLUSION: These results showed that in an open-field setting buspirone appears to have a dual effect. The reduced activity and increase in time spent in the center areas are indicative of both an anxiogenic and an anxiolytic effect, respectively. This was found in both open-field settings, suggesting that the effects of buspirone are independent of the anxiety level.

Clin Neuropharmacol. 2008 Jul-Aug; 31(4): 204-20
Gibel A, Ritsner MS

OBJECTIVE: Two questions were addressed in the present report: whether cognitive improvement would occur during 12-month ziprasidone treatment and whether the changes in cognitive functioning are dependent of changes in the illness-related variables. METHODS: Seventy schizophrenia patients with persistent symptoms or troublesome side effects were assigned to a 12-month, open-label, flexible-dosage (40-160 mg/d) trial. Outcome measures were taken at baseline, 6, and 12 months and included the Mindstreams Computerized Cognitive Battery, the Wisconsin Card Sorting Test, the Clinical Global Impression Scale, the Positive and Negative Syndrome Scale, and the Extrapyramidal Symptom Rating Scale. RESULTS: Baseline performance was impaired across all cognitive tasks on average without significant differences between 32 completers and 38 discontinued patients. At the end of the study, significant improvement in performance of executive functions, attention, and information processing domains among ziprasidone-completed patients was observed. The effect sizes for these changes were moderate (0.61). Improvement in the executive performances was associated with a reduction in the severity of positive, activation, and dysphoric mood symptoms but was unrelated to the ziprasidone daily dose, Clinical Global Impression Scale and Extrapyramidal Symptom Rating Scale scores, and concomitantly prescribed antidepressants, Anxiolytics, mood stabilizers, or antiparkinson drugs. CONCLUSIONS: Ziprasidone had a long-term neurocognitive effect among patients with chronic schizophrenia undergoing the usual care. This effect tended to increase over time and was associated, at least partly, with changes in symptoms, but not with changes in the severity of illness, side effects, the ziprasidone daily dose, and concomitant medicines.

J Acquir Immune Defic Syndr. 2008 Sep 1; 49(1): 61-3
Quereda C, Corral I, Moreno A, Pérez-Elías MJ, Casado JL, Dronda F, Rodríguez-Sagrado MA, Hernández B, Moreno S

BACKGROUND:: Mood disorders and other neuropsychiatric disorders are common adverse events limiting tolerability of alpha-interferon (IFN) therapy for hepatitis C virus (HCV). Because efavirenz (EFV) frequently produces neuropsychiatric side effects, we studied the effect of EFV in the incidence of these side effects in HIV/HCV patients receiving IFN. METHODS:: Prospective cohort of HIV/HCV patients receiving IFN and ribavirin. Adverse events and concomitant medications were systematically recorded once monthly. RESULTS:: Among 266 HIV/HCV patients starting a course of IFN (91% pegylated IFN) plus ribavirin, 53 (20%) received concomitant EFV and 213 (80%) did not. Most EFV patients (92%) were already on EFV before starting IFN (mean 26 months). Neuropsychiatric side effects were frequent, without significant differences between both groups (79% vs 65%, P = 0.051), and only 10 patients discontinued IFN. Mood disorders were reported more frequently in EFV patients (36% vs 23%, P = 0.046), but antidepressant therapy use was similar in both groups. The incidence of anxiety, insomnia, irritability, headache or prescription of Anxiolytics or hypnotics was similar. CONCLUSIONS:: Neuropsychiatric adverse events are common in HIV/HCV patients receiving IFN, usually mild or moderate. EFV may favor symptoms of mood disorders, although it was not related to an increased risk of significant depression requiring specific treatment.

Drugs Aging. 2008; 25(8): 693-706
Carey IM, De Wilde S, Harris T, Victor C, Richards N, Hilton SR, Cook DG

BACKGROUND: Potentially inappropriate prescribing (PIP) in older people has been identified as a substantial problem, but few large population-based studies have investigated the underlying factors that predict it. OBJECTIVE: To: (i) examine trends in PIP in UK older primary care patients; and (ii) assess factors associated with PIP. METHODS: An analysis of routine, anonymized, computerized patient records of 201 UK general practices providing data to the DIN-LINK database between 1996 and 2005, which included approximately 230 000 registered patients per year aged > or = 65 years. The main outcome measures were the number of different drugs prescribed per patient annually and the percentage of patients prescribed a PIP drug (modified 2003 Beers criteria). These were assessed for all drugs, and then for selected sub-classes (analgesics, antidepressants and sedatives/Anxiolytics). RESULTS: Whilst the number of drugs prescribed per patient increased, the percentage of subjects receiving a PIP drug declined from 32.2% in 1996 to 28.3% in 2005, largely due to a fall in co-proxamol (dextropropoxyphene/paracetamol [acetaminophen]) prescribing. In 2005, female gender, being older, more socio-economically deprived or in a care home were strongly associated with PIP. However, the number of drugs prescribed was strongly associated with these variables and the strongest predictor of PIP; adjusting for number of drugs dramatically reduced the strength of all other associations except female gender with PIP. Factors predicting PIP in drug sub-groups were similarly reduced when adjusted for polypharmacy. However, some age trends remained: in the oldest group (aged > or = 85 years), PIP of analgesics was less likely (odds ratio [OR] = 0.70, 95% CI 0.66, 0.75) while PIP of antidepressants was more likely (OR = 1.39, 95% CI 1.28, 1.51). CONCLUSION: PIP amongst older people in the UK, although declining, remains at a high level. The association of PIP with age, deprivation and care homes is largely explained by the higher overall prescribing rates in these groups. The overall rise in prescribing emphasizes that polypharmacy does not necessarily increase PIP and attempts to reduce PIP by focusing on polypharmacy have not been successful. Reductions in PIP have previously been achieved by introducing national guidelines (e.g. co-proxamol), but might also be achieved by alerting practitioners at the point of prescribing.

Crit Care Med. 2008 Aug; 36(8): 2479-80
Easley RB, Nichols DG

Przegl Lek. 2008; 65(2): 92-5
Pawełczyk T, Kłoszewska I

Clinicians perceive psycho-farmacotherapy as a real challenge mainly because of numerous adverse effects and drug interacions that may lead to potential life threatening consequences. The amount information that must be taken into account while prescribing psychotropic drugs grows day by day and it is really difficult to stay well informed. Food, like grapefruit juice (GJ), is also a significant source of interactions, which is sometimes forgotten. Grapefruit contains active bioflavonoids that may change bioavailability of many medications and raise its concentrations above toxic levels. The mechanism of interaction is complex and connected with the influence of GJ active ingredients on prehepatic metabolism and enteric absorption pathways using p-glicoprotein (PGP) and organic anion transporting polipeptide (OATP). The main direction of GJ action is inhibition of cytochrome P450 1A2 and 3A4 isoforms. A wide range of medicines used in daily psychiatric practice undergoes phase I oxidation with CYP 3A4 and 1A2 i.e.: Anxiolytics, antidepressants, mood stabilizers, antipsychotics and procognitive compounds. It raises the potential risk of dangerous interactions with grapefruit juice. GJ is generally contraindicated to patients taking psychotropics and it is advised to inform patients about described interaction.