Frontiers in Clinical Drug Research - CNS and Neurological Disorders

The diseases of drug addiction and alcoholism are characterized by a transition from experimental and recreational use to uncontrolled and compulsive intake, often accompanied by chemical dependence. The primary therapeutic target of drug abuse is the persistent craving experienced by abstinent patients that precedes relapse to drug taking. Growing clinical and preclinical evidence indicates negative affect and dysphoria as important contributors to drug and alcohol craving. Due to the high comorbidity between drug use disorders and other psychological disorders, including depression and anxiety, there is an interest in the potential use of readily available antidepressant drugs as preventative treatments against drug and alcohol relapse. This chapter provides an overview of preclinical and clinical research investigating these indications, and explains the animal models used to obtain information about the treatment potential of various pharmaceutical compounds. Overviews of primary neurotransmitter targets and pharmacokinetic aspects of the therapeutic compounds are provided throughout the chapter.

Several therapeutic agents are currently used as first-line agents in the management of multiple sclerosis (MS) including interferon-beta 1a, interferon-beta 1b, and glatiramer acetate. Currently approved second-line agents include natalizumab, cyclophoshamide, mitoxantrone and the oral agent fingolimod. In addition, there are several emerging therapeutic agents including laquinimod, alemtuzumab, teriflunomide, ocrelizumab, and fumaric acid that are presently being evaluated in clinical trials. While these new treatments have the potential to have a powerful effect on MS disease activity, many also carry significant risks of adverse events or tolerability concerns. With the expanding repertoire of available MS therapies clinicians will have to carefully consider efficacy, safety, and tolerability when engaging with patients to make treatment decisions. In this article, we describe the mechanism of action, efficacy data, and side effect profile of MS therapies with a focus on the newly emerging agents.

Gliomas account for about 45% of all primary central nervous system tumors and 77% of all malignant primary cerebral tumors. Recent studies in molecular biology have better depicted the mechanisms involved in the genesis of cerebral gliomas. It is now generally understood that tumor genesis occurs either by over-expression of oncogenes or inactivation of tumor suppressor genes. The two main gene groups involved in brain tumor development are proto-oncogenes and tumor suppressor genes, respectively up-regulated and downregulated during the tumor initiation and progression. It's evident that the modulation of gene expression at more levels, such as DNA, mRNA, proteins and transduction signal pathways, may be the most effective modality to downregulate or silence specific genic functions. Nowadays, an efficacious strategy in the gliomas treatment does not yet exist. In series of patients affected by malignant gliomas mortality is still close to 100% and the survival rate in glioblastoma multiforme patients is less than 1 year.

A potential and future therapeutic approach in gliomas treatment is represented by antisense therapy targeting different antigens or signal pathway of growth factors and their receptors like IGF-I, TGF-beta2 or EGF. The antisense strategy is based on use of antisense oligonucleotides (gene therapy sensu strictu) or of antisense expressing vectors (cell gene therapy). The clinical results obtained using antisense therapy are often similar than those obtained by use of certain inhibitors (i.e. imatinib, getifinib) including antibodies (avastin) targeting the growth factors and their downstream element of signaling pathways. The results are especially interesting if applying the combined techniques of antisense and/or inhibitors with chemotherapy. Using either the approach of inhibitors of growth factors and their receptors, especially of EGF, or the approach of antisense IGF-I and anti TGF-beta inducing anti-tumor response, the median survival of glioblastoma patients can reach currently two years if combined with chemotherapy (temozolomide). These results constitute a progress as compared to classical treatment and underline the value of molecular biology based gene therapy, especially immune-gene therapy.

In this chapter we describe the most relevant findings of antisense oligonucleotides application in gliomas treatment pointing out the attention on effectiveness, delivery system possibilities, targeting modalities and safety of this therapeutic strategy.

Posttraumatic stress disorder (PTSD) is a complex disorder associated with an intricate biological and psychological symptom profile and various common comorbidities. Despite the availability of various treatment strategies, PTSD is often difficult to treat. Several researchers have proposed that impaired fear extinction is involved in the pathophysiology of PTSD. Therefore, enhancing fear extinction using cognitive enhancers could be a new modality for the treatment of PTSD. To date, various cognitive enhancers that alter GABAergic, glutamatergic, dopaminergic, noradrenergic, and cannnabinoid pathways have been investigated in animal models of fear extinction. The present review focuses on D-cycloserine (DCS), a partial agonist of N-methyl-D-aspartate (NMDA) receptors, and on histone deacetylase (HDAC) inhibitors. Herein, we provide an overview of the effects of these agents, the clinical implications and drawbacks associated with their use, and directions for future research. Many preclinical and clinical studies of DCS have demonstrated a facilitating effect on fear extinction. Thus, among various cognitive enhancers, DCS seems to be the most promising agent for the treatment of PTSD. However, recent clinical studies of DCS in PTSD have not demonstrated sufficient efficacy. Several preclinical studies have also revealed that administration of HDAC inhibitors with exposure therapy can enhance fear extinction. However, no clinical studies have been conducted to assess the efficacy of HDAC inhibitors in PTSD; therefore, it is recommended that clinical trials of HDAC inhibitors be conducted in the future.

Accumulated evidence indicates that lactate plays a significant role in energy production in the brain, especially during acute neural activation. The astrocyte-neuron lactate shuttle hypothesis has been proposed to explain how lactate is supplied to neurons. Furthermore, the ability of lactate to protect neurons against excite toxicity and oxidative stress has been reported. There is a growing interest in the role for serotonin (5-HT)_1A receptors in the treatment of negative symptoms and cognitive disturbances of schizophrenia. This is based on clinical evidence that 5-HT_1A agonists, such as tandospirone, perospirone, and lurasidone, improve cognitive function in patients with the illness. Data from rodent studies also support the hypothesis that stimulation of 5-HT_1Areceptors is advantageous in treating cognitive deficits of schizophrenia.

Rats experiencing transient N-methyl-D-aspartate receptor (NMDA-R) blockade during the neonatal stage show reduction of the stress-induced increase in extracellular lactate concentrations in the medial prefrontal cortex around the pubertal period. Treatment with 5-HT_1A receptor agonists, such as tandospirone, reversed the decreased lactate production in these model animals. These observations indicate that lactate metabolism provides a novel probe for the development of psychotropic compounds to treat core symptoms of schizophrenia.

The armamentarium to treat epilepsy includes today more than twenty drugs. These are classically distinguished as standard, traditional or first generation antiepileptic drugs (AEDs), which include phenobarbital, phenytoin, carbamazepine, valproic acid, ethosuximide and benzodiazepines, and new or second generation AEDs, which are vigabatrin, lamotrigine, felbamate, gabapentin, oxcarbazepine, tiagabine, topiramate, stiripentol, pregabalin, levetiracetam, rufinamide, zonisamide. More recently, other four compounds have been introduced, i.e., lacosamide, retigabine, eslicarbazepine acetate and perampanel, also defined as third generation AEDs. The mechanism of antiepileptic action is mainly mediated by increase in inhibitory GABA activity and/or prolongation of sodium and/or calcium channel inactivation. From a pharmacokinetic point of view, the most relevant difference characterizing a number of the recent AEDs as compared to the traditional ones is the lack of or a milder induction of hepatic enzymes with consequent reduced risk of drug-drug interactions. Concerning therapeutic features, valproic acid exhibits the broadest spectrum of action and still remains the only AED which can be used to treat all types of seizures, from absences and other primarily generalized seizures to focal ones, and almost all syndromes. Among the recent compounds, lamotrigine, topiramate, levetiracetam and zonisamide have shown to be efficacious in primarily generalized seizures and in some idiopathic generalized epilepsies, but their effect against absence seizures is less potent than that of valproic acid or even irrelevant. All AEDs, except ethosuximide, exhibit similar efficacy against focal seizures and, apart from traditional drugs, lamotrigine, oxcarbazepine, gabapentin, topiramate and levetiracetam, and ZNS in Europe, have the indication of mono-therapy. Some of the new compounds have specific paediatric indications: vigabatrin against infantile spasms in West syndrome, felbamate and rufinamide against mixed seizures in the Lennox-Gastaut syndrome, and stiripentol against some types of seizures in Dravet syndrome. In spite of this variety of AEDs, the percentage of patients with refractory epilepsy has not changed over the last 50 years and is still stabilized around 30-40%. Adverse events are observed in one-third of patients on AED therapy. Frequent, unspecific and usually dose dependent CNS side effects occur with almost all AEDs and encompass sedation, somnolence, fatigue, and dizziness, usually attenuating or even disappearing over time. Acute idiosyncratic effects, such as skin rush, may be particularly troubling and may configure a hypersensitivity syndrome with rapid degeneration to a severe and even life-threatening condition. Felbamate and vigabatrin are used exceptionally because of high incidence of aplastic anemia and liver failure occurring with the first and irreversible loss of visual field occurring with the second one. Subtle and slowly developing adverse effects, like bone mineral density reduction associated especially with traditional enzyme-inducing AEDs, require a continuous monitoring of the patient clinical condition. Antiepileptic therapy has special implications for women of child bearing age with regard to contraception, pregnancy and teratogenicity. There is some evidence that teratogenic effects, particularly frightening with valproic acid, with > 400mg/day dose of carbamazepine, and with polytherapies, are less frequent with lamotrigine. Given the large number of available AEDs, opportunities to tailor drug therapy on the individual patient are various. Treatment decisions, however, are complex and need to be individualised on the basis of careful evaluation of a number factors related to drug, disease and the patient. Choice of first-line therapy for a specific form of epilepsy, the time at which the drug should be started, and which strategy is most appropriate after failure of the first drug are key decision steps. Patient-specific factors include age, sex, childbearing potential, co-morbidities, and concomitant medications. Future directions include discovery of drugs with an improved safety profile, with more potent anti-seizure effect, able to prevent epileptogenesis and, possibly, to interact with specific genetic substrates.

Schizophrenia is a lifelong devastating mental disorder characterized by positive, negative, affective, and cognitive symptoms. Cognitive impairment is a core feature of the illness and exerts a great influence on long-term outcomes, including quality of life, social, and occupational functioning. Currently, effective treatments for cognitive deficits are thought to be the greatest unmet needs. Numerous recent clinical trials have suggested only modest benefits on cognitive function in schizophrenia relative to first- and second-generation antipsychotics when dosed properly. Moreover, both classes appear to have largely similar efficacy. Adjunctive cognitive enhancing agents with various molecular targets should be pursued, because they can be viable future treatments for cognitive impairment associated with schizophrenia. In line with this goal, a wide range of compounds have been developed and some of them have been evaluated in randomized clinical trials. This article provides a critical updated review of the effects of currently available antipsychotics and developing cognitive enhancers on cognition in schizophrenia.

Autism spectrum disorders (ASD) are neurodevelopmental disorders with reduced cortical functional connectivity relating to social cognition. The evaluation of pharmacological treatment in ASD has been directed at abnormal developmental trajectories or toward enhancing plasticity during the development of brain. Accumulating evidence indicates that the gross abnormalities in these neurotransmitter systems such as serotonin and dopamine systems may underpin the neurophysiologic mechanism of ASD. Particularly, the serotonergic system may be especially implicated in pathophysiology of social impairment of ASD. Abnormal functional connectivity, which affects the delivery of afferent signals, may be involved in the pathophysiology of autism spectrum disorders (ASD). Arachidonic acid in the nervous system is important in signal transduction related to neuronal maturation. Risperidone solution, a novel antipsychotic which combined dopaminergic and serotonergic action, has shown to be effective in impaired social interaction. Oxytocin may mediate the benefits of positive social interaction and emotions. It is therefore worth noticing that risperidone solution, intranasal administration of oxytocin, and dietary supplementation with arachidonic acid have been found promising to maximize social interaction. Atypical antipsychotics ariprazole and SSRI fluoxetine exhibited their efficacy in treating some aspects of social relatedness or the core deficits of communication and socialization. There is evidence that abnormalities exist in peptide systems such as neuropeptides. GABAB antagonist STX209 has proved its efficacy in improving the ABC-irritability and Social withdrawal subscales. D-cycloserine exhibited significant improvement on social withdrawal subscale of the ABC in some subjects with ASD. It is hoped that improved strategies for early identification with phenotypic characteristics and biological markers (e.g., brain physiological and biochemical changes) would remarkably improve the effectiveness of treatment.

The evaluation of treatments for ASD needs to be directed towards neurobiological targets known to be important in the brain's response to abnormal developmental trajectories or toward enhancing plasticity during the high sensitive period in gene-environment interaction (epigenetic mechanism). Further research towards neurobiology and effective treatments for ASD is required.

Major depressive disorder (MDD) in adolescents, which tends to be a particularly malignant and intractable condition, somatic condition, increases the likelihood of recurrence and is a major cause of suicide attempt and death, and chronicity in adulthood. Increases in alpha- or theta- band activity, or asymmetries in the alpha band may predict successful responses to treatment with selective serotonin uptake inhibitors. Reward-related brain function, such as greater reactivity in the lower medial prefrontal cortex, and greater right-side frontal brain activity predict MDD symptoms. Greater activation of both the amygdale, related to functional connections, has been reported as the neurobiological bases of adolescent MDD. An increased imbalance of resting-state brain activity between the frontal cognitive control system and the limbic-striatal emotional processing system was recognized. Inherited risks, such as developmental factors and psychosocial adversity, interact to increase the risk of depression through hormonal factors and the associated perturbation of the relevant neural pathway. These multiple complex pathophysiological factors might contribute to the development of a particularly malignant and intractable adolescent depression, and cause increased likelihood of recurrence and chronicity in adulthood.

Daily doses of escitalopram and fluoxethine (10-20 mg) have been demonstrated as effective in treating adolescents with MDD. However, a recent review article has proposed that escitalopram should be considered as a second-line treatment option for adolescents with MDD. It should be noted that escitalopram treatment has been recommended on the basis of a single study of positive behavioral cognitive therapy because of lack of evidence.