The pharmacodynamic effects of combined administration of flibanserin and alcohol.

WHAT IS KNOWN AND OBJECTIVE: Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. METHODS: In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4 ). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. RESULTS: In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. WHAT IS NEW AND CONCLUSION: Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.

Innovative solutions to novel drug development in mental health.

There are many new advances in neuroscience and mental health which should lead to a greater understanding of the neurobiological dysfunction in neuropsychiatric disorders and new developments for early, effective treatments. To do this, a biomarker approach combining genetic, neuroimaging, cognitive and other biological measures is needed. The aim of this article is to highlight novel approaches for pharmacological and non-pharmacological treatment development. This article suggests approaches that can be taken in the future including novel mechanisms with preliminary clinical validation to provide a toolbox for mechanistic studies and also examples of translation and back-translation. The review also emphasizes the need for clinician-scientists to be trained in a novel way in order to equip them with the conceptual and experimental techniques required, and emphasizes the need for private-public partnership and pre-competitive knowledge exchange. This should lead the way for important new holistic treatment developments to improve cognition, functional outcome and well-being of people with neuropsychiatric disorders.

Psychotherapy as an epigenetic 'drug': psychiatric therapeutics target symptoms linked to malfunctioning brain circuits with psychotherapy as well as with drugs.

WHAT IS KNOWN AND OBJECTIVE: Psychotherapy has traditionally competed with psychopharmacology. As drugs have become the more dominant treatment in psychiatry and primary care, this approach is increasingly criticized as limited in scope, lacking in robust outcomes and too heavily influenced by the pharmaceutical industry. Our objective is to show that recent advances in neurobiology are clarifying that learning and environmental experiences, such as psychotherapy, change brain circuits as do drugs. The leading notion of how therapeutic effects occur in psychiatric disorders is that they happen when symptoms are reduced by improving the efficiency of information processing in hypothetically malfunctioning brain circuits. COMMENT: With this formulation of psychiatric symptoms and their relief, it is not surprising that both psychotherapy and psychopharmacology can be clinically effective for treating psychiatric disorders, or indeed that combining them can be therapeutically synergistic. Psychotherapy, including a new spinoff of cognitive behavioural therapy called trial-based therapy, like many other forms of learning, can hypothetically induce epigenetic changes in brain circuits that can enhance the efficiency of information processing in malfunctioning neurons to improve symptoms in psychiatric disorders, just like drugs. WHAT IS NEW AND CONCLUSION: Psychotherapies can be conceptualized as epigenetic 'drugs', or at least as therapeutic agents that act epigenetically in a manner similar or complementary to drugs. These findings are leading to a paradigm shift in psychiatry such that psychotherapy is experiencing a come-back as various standardized, brief, goal-directed psychotherapies are being integrated with drug treatment of psychiatric disorders by psychopharmacologists who have traditionally relied on a drugs-only approach.

Searching for perfect sleep: the continuing evolution of GABAA receptor modulators as hypnotics.

The non-benzodiazepine GABA(A) receptor modulators ('Z-drugs') - zaleplon, zolpidem, zopiclone and eszopiclone - have become the accepted treatments for insomnia where they are available. However, recent randomized, placebo-controlled trials suggest that, for these drugs, there may be particular efficacy and tolerability profiles and distinct clinical outcomes in specific patient populations. This is particularly apparent when hypnotic/ selective serotonin reuptake inhibitor co-therapy is used to treat patients with co-morbid insomnia and psychiatric disorders, as patient recovery appears to be accelerated and enhanced by some drugs but not others. Emerging evidence of why this should be the case is that these hypnotic drugs may differ significantly from each other in their pharmacodynamic and pharmacokinetic profiles. Functional selectivity for specific GABA(A) receptor subtypes may determine each drug's clinical attributes, while the pharmacokinetic characteristics of Z-drugs also determine to a large extent how they perform in the clinic. For example, activity at GABA(A) alpha 1 receptor subtypes may be associated with sedative effects, whereas activity at alpha 2 and alpha 3 receptor subtypes may be associated with anxiolytic and antidepressant effects. In summary, the distinct clinical outcomes of zaleplon, zolpidem, zopiclone and eszopiclone may be explained by each drug's unique GABA(A) receptor subunit selectivity and pharmacokinetic profile. Further investigation of GABA( A) receptor subtype effects would help to increase understanding of current hypnotic drug effects, while knowledge of each drug's specific binding profile should enable clinicians to tailor treatment to individual patient's needs.

The metabolic syndrome and schizophrenia.

OBJECTIVE: To summarize the accumulated data on metabolic syndrome prevalence in patients with schizophrenia, examine evidence for a biological contribution of the mental illness to metabolic risk and review novel options available for management of prediabetic states. METHOD: A Medline search using metabolic syndrome, insulin resistance and insulin sensitivity cross-referenced with schizophrenia was performed on articles published between 1990 and May 2008. RESULTS: Recent evidence indicates that schizophrenia increases predisposition towards metabolic dysfunction independent of environmental exposure. Both fasting and non-fasting triglycerides have emerged as important indicators of cardiometabolic risk, while metformin, thiazolidinediones and GLP-1 modulators may prove promising tools for managing insulin resistance. CONCLUSION: Because of lifestyle, disease and medication effects, schizophrenia patients have significant risk for cardiometabolic disease. Routine monitoring, preferential use of metabolically neutral antipsychotics and lifestyle education are critical to minimizing risk, with a possible role for antidiabetic medications for management of insulin resistant states that do not respond to other treatment strategies.

Which comes first: atypical antipsychotic treatment or cardiometabolic risk?

OBJECTIVE: To provide an overview for practicing clinicians on the pharmacological basis of cardiometabolic risk induced by antipsychotic drugs in patients with serious mental illness, to propose hypotheses to explain these risks and to give tips for managing cardiometabolic risk during antipsychotic treatment. METHOD: A MEDLINE search using terms for atypical antipsychotics (including individual drug names), metabolic, cardiovascular, weight gain and insulin resistance, cross-referenced with schizophrenia was performed on articles published between 1990 and May 2008. RESULTS: Strong evidence exists for significant cardiometabolic risk differences among several antipsychotic agents. Histamine H1 and serotonin 5HT2C antagonism are associated with risk of weight gain, but receptor targets for dyslipidemia and insulin resistance have not yet been identified. Convincing data indicate that hypertriglyceridemia and insulin resistance may occur in the absence of weight gain with certain antipsychotics. CONCLUSION: Although lifestyle and genetics may contribute independent risks of cardiometabolic dysfunction in schizophrenia and other serious mental illness, antipsychotic treatment also represents an important contributor to risk of cardiometabolic dysfunction, particularly for certain drugs and for vulnerable patients. Mental health professionals must learn to recognize the clinical signposts indicating antipsychotic-related cardiometabolic problems to forestall progression to type II diabetes, cardiovascular events and premature death.

Negative symptoms of schizophrenia: a problem that will not go away.

OBJECTIVE: Negative symptoms of schizophrenia are a common, enduring, and debilitating component of the psychopathology of schizophrenia. Although efforts thus far to elucidate a distinct schizophrenia subtype based upon negative symptoms have yielded mixed results, there are nevertheless neurobiological correlates of the negative symptom typology. METHOD: A review of nosology, typology, and assessment tools for determining core negative symptoms in schizophrenia. RESULTS: Negative symptoms can be difficult to evaluate objectively. Current rating scales 'capture' key domains of negative symptoms, in spite of considerable overlap between these domains. However, each objective assessment trades off methodological rigor and detail against brevity of assessment and ease of use. CONCLUSION: The description of new methods for measuring these devastating symptoms, coupled with the ongoing development of novel antipsychotics and agents that augment antipsychotics have fuelled renewed interest in the evaluation of negative symptoms and optimism that better treatments for negative symptoms can be found.

Pharmacological treatment of negative symptoms of schizophrenia: therapeutic opportunity or cul-de-sac?

UNLABELLED: Negative symptoms of schizophrenia are debilitating and they contribute to poor outcome in schizophrenia. Initial enthusiasm that second-generation antipsychotics would prove to be powerful agents to improve negative symptoms has given way to relative pessimism that the effects of current pharmacological treatments are at best modest. METHOD: A review of the current 'state-of-play' of pharmacological treatments for negative symptoms in schizophrenia. RESULTS: Treatment results to date have been largely disappointing. The evidence for efficacy of second-generation antipsychotics is reviewed. CONCLUSION: The measurement and treatment trials methodology for the evaluation of negative symptoms need additional refinement before therapeutic optimism that better treatments for negative symptoms can be realized.

A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation.

The atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have become first-line treatment for schizophrenia because they reduce the positive symptoms of psychosis but do not have a high incidence of extrapyramidal symptoms. However, these agents, like other antipsychotics, may take as long as 16 or more weeks to produce a response, and even with prolonged treatment are unlikely to evoke responses greater than 50% improvement in symptoms. This has led to the experimental use of high atypical antipsychotic doses, antipsychotic polypharmacy, and augmentation with other psychotropic drugs, all of which occur commonly in clinical practice. This article reviews the current evidence for these increasingly common means of treating schizophrenia and psychosis, with particular emphasis on polypharmacy and augmentation. To date, there are only two controlled studies of antipsychotic polypharmacy involving an atypical antipsychotic; the rest of the data are uncontrolled trials and case reports that describe a mixture of positive and negative findings. One multicenter, double-blind trial shows a faster onset of action when divalproex is added to risperidone or olanzapine than with antipsychotic monotherapy. A small double-blind study demonstrates efficacy when lamotrigine is added to clozapine. The rest of the data on augmentation with anticonvulsants are uncontrolled, and most report adverse effects. With the exception of divalproex, there are currently no compelling data to justify the use of antipsychotic polypharmacy or augmentation. Existing evidence suggests that the best treatments for schizophrenia and psychosis may be long-term trials of a sequence of atypical antipsychotic monotherapies at therapeutic doses.

"Hit-and-run" actions at dopamine receptors, part 1: Mechanism of action of atypical antipsychotics.

Either 5-HT2A antagonism or fast dissociation from D2 receptors may define an atypical antipsychotic. To have little or no motor symptoms from an antipsychotic, it is clear that D2 receptor binding in the striatum must be less than that caused by conventional antipsychotics. Pure 5-HT2A antagonism by itself does not result in robust antipsychotic actions. However, 5-HT2A antagonism can reduce D2 antagonism and thereby reduce motor symptoms without reversing antipsychotic actions. If, however, this 5-HT2A antagonism is overwhelmed by too much D2 antagonism, it cannot result in such atypical antipsychotic actions. Another route to reducing D2 receptor binding appears to be to shorten binding time, also known as rapidly dissociating from the D2 receptor. Many of the agents with atypical antipsychotic clinical properties hit the D2 receptor hard enough to cause antipsychotic effects and then run before they cause extrapyramidal side effects.

Natural estrogen as an antidepressant for women.

Recent well-controlled studies suggest that estrogen has antidepressant actions in perimenopausal women. Estrogen may also have antidepressant actions in postpartum women and across the life cycle for women who are resistant to treatment with various antidepressants. The question, however, of which depressed women to treat with antidepressants, which with estrogen, and which with both remains unanswered.

Effectiveness of St John's wort in major depression: a randomized controlled trial.

CONTEXT: Extracts of St John's wort are widely used to treat depression. Although more than 2 dozen clinical trials have been conducted with St John's wort, most have significant flaws in design and do not enable meaningful interpretation. OBJECTIVE: To compare the efficacy and safety of a standardized extract of St John's wort with placebo in outpatients with major depression. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted between November 1998 and January 2000 in 11 academic medical centers in the United States. PARTICIPANTS: Two hundred adult outpatients (mean age, 42.4 years; 67.0% female; 85.9% white) diagnosed as having major depression and having a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 20. INTERVENTION: Participants completed a 1-week, single-blind run-in of placebo, then were randomly assigned to receive either St John's wort extract (n = 98; 900 mg/d for 4 weeks, increased to 1200 mg/d in the absence of an adequate response thereafter) or placebo (n = 102) for 8 weeks. MAIN OUTCOME MEASURES: The primary outcome measure was rate of change on the HAM-D over the treatment period. Secondary measures included the Beck Depression Inventory (BDI), Hamilton Rating Scale for Anxiety (HAM-A), the Global Assessment of Function (GAF) scale, and the Clinical Global Impression-Severity and -Improvement scales (CGI-S and CGI-I). RESULTS: The random coefficient analyses for the HAM-D, HAM-A, CGI-S, and CGI-I all showed significant effects for time but not for treatment or time-by-treatment interaction (for HAM-D scores, P<.001, P =.16, and P =.58, respectively). Analysis of covariance showed nonsignificant effects for BDI and GAF scores. The proportion of participants achieving an a priori definition of response did not differ between groups. The number reaching remission of illness was significantly higher with St John's wort than with placebo (P =.02), but the rates were very low in the full intention-to-treat analysis (14/98 [14.3%] vs 5/102 [4.9%], respectively). St John's wort was safe and well tolerated. Headache was the only adverse event that occurred with greater frequency with St John's wort than placebo (39/95 [41%] vs 25/100 [25%], respectively). CONCLUSION: In this study, St John's wort was not effective for treatment of major depression.