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Bipolar disorder is a pathological disturbance of mood, characterized by waxing and waning manic, depressive and, sometimes distinctly mixed states. A diagnosis of bipolar disorder can only be made with certainty when the manic syndrome declares itself. Most individuals who are diagnosed with this disorder will experience both poles of the illness recurrently, but depressive episodes are the commonest cause of morbidity and, indeed, of death by suicide. Twin, adoption and epidemiological studies suggest a strongly genetic aetiology. It is a genetically and phenotypically complex disorder. Thus, the genes contributing are likely to be numerous and of small effect. Individuals with bipolar disorder also display deficits on a range of neuropsychological tasks in both the acute and euthymic phases of illness and correlations between number of affective episodes experienced and task performance are commonly reported. Current self-report and observer-rated scales are optimized for unipolar depression and hence limited in their ability to accurately assess bipolar depression. The development of a specific depression rating scale will improve the assessment of bipolar depression in both research and clinical settings. It will improve the development of better treatments and interventions. Guidelines support the use of antidepressants for bipolar depression. With regard to the adverse effects of antidepressants for bipolar depression, double-blind, placebo-controlled data suggest that antidepressant monotherapy or the addition of a tricyclic antidepressant may worsen the course of bipolar disorder. Importantly, adjunctive psychotherapies add significantly (both statistically and clinically) to the efficacy of pharmacological treatment regimens. The successful management of bipolar disorder clearly demands improved recognition of bipolar disorder and effective long-term treatment for bipolar depression as well as mania.

This study evaluated the anxiolytic efficacy, safety and tolerability of a flexible dose of venlafaxine extended release (ER) compared with placebo and paroxetine in the short-term treatment of generalized social anxiety disorder (SAD). Adult outpatients with generalized SAD (n = 434) were randomized to receive capsules of venlafaxine ER 75 mg to 225 mg/day, paroxetine 20 mg to 50 mg/day, or placebo for 12 weeks. The primary efficacy variable was the Liebowitz social anxiety scale total score. Secondary efficacy variables included the patient-rated social phobia inventory and the proportion of responders in each group (a responder was defined as having a clinical global impression-improvement score of 1 or 2). Treatment with venlafaxine ER was associated with significantly greater improvement than treatment with placebo for all primary and secondary efficacy variables (p < 0.05). No significant differences in primary or secondary efficacy variables were observed between the venlafaxine ER and paroxetine groups. The week 12 response rates were 69%, 66% and 36% for the venlafaxine ER, paroxetine and placebo groups, respectively. Both active treatments were generally well tolerated and were associated with a similar incidence of adverse events. This study shows that venlafaxine ER is an effective, safe and well-tolerated drug treatment for SAD.

Both haemophilia A and B are X-linked recessive disorders and therefore occur almost exclusively in males. The genes for both factors VIII and IX have been mapped to the distal end of the long arm of the X chromosome, bands Xq28 and Xq27.1, respectively. The Factor VIII gene comprises 186 kb DNA with 9 kb of exon of DNA which encodes an mRNA of nearly 9 kb. The Factor IX gene is 34 kb in length and the essential genetic information is present in eight exons which encode 1.6 kb mRNA. In gene therapy, genetic modification of the target cells can be either ex vivo or in vivo. The advantage of the ex vivo approach is that the genetic modification is strictly limited to the isolated cells. In the in vivo approach, the integrity of the target tissue is maintained but the major challenge is to deliver the gene to the target tissue. The use of improved retroviral and adenovirus-based vectors for gene therapy has produced clinically relevant levels of human factor VIII in mice and haemophilic dogs. If further improvements can increase the persistence of expression and decrease the immunological responses, phase I clinical trials in patients can be considered.

Characteristic features of post-traumatic stress disorder (PTSD) include intrusive memories, avoidance, memory and concentration difficulties, and hyperalertness. Neuropsychological investigations of individuals with PTSD have suggested global and specific impairments of performance on standardized tests of memory. The use of the Emotional Stroop test has shown that trauma-related words are a sensitive measure of clinical state in PTSD patients. The Stroop paradigm has also shown that patients with PTSD appear to be characterized by implicit, explicit and autobiographical memory impairment. Available treatments for chronic post-traumatic stress disorder include cognitive-behaviour therapy, psychodynamic therapy and pharmacotherapy. Whereas drug treatment alone can rarely alleviate the suffering in PTSD, it appears to be most useful as an adjunct to psychotherapy. Tricyclic antidepressants are generally thought to be effective in alleviating symptoms, including nightmares, depression, sleep disorders and startle reactions, but are less able to relieve numbing. On the other hand, selective re-uptake blockers may be effective in decreasing numbing. However, rigorous clinical trials with double-blind placebo-controlled designs need to be performed to confirm these results. With new scientific discoveries in the understanding of PTSD, a new generation of pharmacological treatment is likely to emerge. (Int J Psych Clin Pract 2000; 4:3-18).

Insomnia is a frequent complaint in the elderly population. Hypnotic agents, including benzodiazepines, with longer pharmacological half-lives have been associated with side effects, including residual sedation, memory impairment, and discontinuation effects. Zaleplon is a short-acting (elimination half-life of 1 hour), non-benzodiazepine hypnotic that acts on the benzodiazepine type 1 site of the gamma-aminobutyric acid type A (GABA(A)) receptor complex. The pharmacology and pharmacokinetics of Zaleplon suggest a safety profile that is improved over other hypnotics. The objective of this placebo-controlled study was to evaluate the efficacy and safety of Zaleplon (5 and 10 mg) in elderly (> or =65 years) outpatients with primary insomnia. This was a multicenter, double-blind, randomised, placebo-controlled 2-week outpatient study. Postsleep questionnaires were used to record subjective sleep variables: sleep latency, sleep duration, number of awakenings, and sleep quality. Zaleplon significantly reduced subjective sleep latency during both weeks of the study with both 5- and 10-mg doses. Subjective sleep quality was improved for significantly more patients treated with zaleplon 10 mg than those treated with placebo during both weeks of treatment. There was a weak indication of rebound insomnia after discontinuation of treatment with the 10-mg dose, but no significant difference in common treatment-emergent adverse events across treatment groups. Zaleplon is an effective and safe hypnotic for the treatment of insomnia in the elderly.

Family, twin and adoption studies suggest that genetic factors play an important role in the aetiology of schizophrenia. The mode of inheritance, however, is complex and non-Mendelian. Although the aetiology of schizophrenia is unknown, it has been hypothesized that the necessary conditions for developing the disease are environmental stress and a vulnerability to psychosis. The implication of dopamine receptors to schizophrenia has been greatly studied. Several linkage and association studies have been performed in an attempt to establish the involvement of dopamine receptors in schizophrenia. However, although no conclusive evidence of linkage or association to any gene has been established, some results, suggestive of linkage for chromosomes 6, 22 and 13, await confirmation from other studies. Concerning association studies, it is also of interest that some studies support an association between schizophrenia and homozygosity at D(3). More work in larger samples is required before conclusive linkage hypothesis or association to a dopamine receptor may be established. Schizophrenic patients have been shown to have significant deficits in a wide range of cognitive processes, including memory, attention, reasoning ability and language. Since cognitive deficits are significant symptoms of schizophrenia which require effective treatment, their assessment in schizophrenic patients and during clinical trials of new potential antipsychotics is highlighted. Cognitive impairment in schizophrenia impedes psychosocial performance and is therefore an especially relevant target variable in the development of new therapeutic approaches. It is most prominent in tasks involving attention, memory and executive functions which are thought to reflect involvement of prefrontal and left-temporal brain areas. Semantic networks in schizophrenic patients with a younger age of onset are observed to be more disorganized and differ significantly to those of control subjects. The need to use broader approaches such as neuropsychological-related measures to identify pertinent phenotypes in non-affected subjects carrying vulnerability genes is also emphasized. Since dopamine receptors are the primary targets in the treatment of schizophrenia, improved therapy may be obtained by drugs that selectively target a particular subtype of dopamine receptor. In the development of novel antipsychotics, D(3) and D(4) receptors have received much attention and this is partly related to the fact that these receptors have a high abundance in brain areas associated with cognitive and emotional functions, such as parts of the limbic system and cortex. Recent studies suggest that atypical neuroleptics may significantly improve the cognitive deficits observed in schizophrenic patients and that atypical neuroleptics such as risperidone appear to improve memory and alertness suggesting that further clinical studies are needed to determine the precise influence of antipsychotics on the cognitive system of schizophrenic patients. Such studies could lead to useful insights as to the potential advantages of the newer antipsychotics which appear to have a sparing or beneficial effect on various components of cognitive function. However, the observation that cortical D(2) receptors are important sites of action for antipsychotics, that the cerebral cortex may harbour the common sites of actions of antipsychotics and that the balancing of the opposing actions of D(1) and D(2) receptor regulation may be an appropriate drug treatment suggests that the adjustment of D(1) receptor levels in the cortex may become an important goal of future antipsychotic generation. Such antipsychotics will be able to treat the positive, negative and cognitive deficits of schizophrenia.

BACKGROUND Zaleplon is a short-acting pyrazolopyrimidine hypnotic with a rapid onset of action. This multicenter study compared the efficacy and safety of 3 doses of zaleplon with those of placebo in outpatients with DSM-III-R insomnia. Zolpidem, 10 mg, was used as an active comparator. METHOD After a 7-night placebo (baseline) period, 615 adult patients were randomly assigned to receive, in double-blind fashion, I of 5 treatments (zaleplon, 5, 10, or 20 mg; zolpidem, 10 mg; or placebo) for 28 nights, followed by placebo treatment for 3 nights. Sleep latency, sleep maintenance, and sleep quality were determined from sleep questionnaires that patients completed each morning. The occurrence of rebound insomnia and withdrawal effects on discontinuation of treatment was also assessed. All levels of significance were p < or = .05. RESULTS Median sleep latency was significantly lower with zaleplon, 10 and 20 mg, than with placebo during all 4 weeks of treatment and with zaleplon, 5 mg, for the first 3 weeks. Zaleplon, 20 mg, also significantly increased sleep duration compared with placebo in all but week 3 of the study. There was no evidence of rebound insomnia or withdrawal symptoms after discontinuation of 4 weeks of zaleplon treatment. Zolpidem, 10 mg, significantly decreased sleep latency, increased sleep duration, and improved sleep quality at most timepoints compared with placebo; however, after discontinuation of zolpidem treatment, the incidence of withdrawal symptoms was significantly greater than that with placebo and there was an indication of significant rebound insomnia for some patients in the zolpidem group compared with those in the placebo group. The frequency of adverse events in the active treatment groups did not differ significantly from that in the placebo group. CONCLUSION Zaleplon is effective in the treatment of insomnia. In addition, zaleplon appears to provide a favorable safety profile, as indicated by the absence of rebound insomnia and withdrawal symptoms once treatment was discontinued.

Abnormalities of circadian rhythms in depressed patients have been noted, including decreased amplitude, distorted waveform, day-to-day instability, and unusual 48 hour periods. Consistent electroencephalographic sleep recording in these patients show a shortened rapid eye movement latency and slow-wave sleep (stages 3 and 4), resulting in an increase in rapid eye movement sleep. This phenomenon appears to be a dependable, measurable marker for diagnosing primary depression. Total sleep deprivation appears to significantly improve mood in a high percentage of depressed patients. Current pharmacological research suggests that drug treatment such as lithium would not affect the intra sleep cycles of the REM stagebut would shift the phase backward and lithium would also shift the phase of circadian rhythm of the daytime sleepiness backward. This paper highlights some of the new approaches for investigating the molecular substrate for the control of circadian rhythmicity and sleep in man and critically examines the hypothesis of the alteration of this mechanism in psychopathology, particularly depression. What is known of the endogenous clock mechanism is discussed with known molecular circadian mechanisms with a view towards understanding how circadian information is transmitted to the rest of the central nervous system and how it is affected in depression.

Glycaemic control in Type 1 diabetes has been proven efficient in preventing microvascular and neurological complications. The assumption that good control of hyperglycaemia may also have significant impact on alleviation of complications in Type 2 diabetes has gained growing support in recent years. Measures such as body weight reduction and exercise improve the metabolic defects, but pharmacological therapy is most frequently used. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase glucose disposal and decrease hepatic glucose output without causing hypoglycaemia. Acarbose helps to spread the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological treatments can improve blood glucose regulation in Type 2 diabetes patients. However, the key to strict glycaemic control with use of exogenous insulin lies in the creation of delivery methods that emulate physiologic insulin secretion. Insulin lispro, a recombinant insulin analogue, is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C-terminus of the B chain. Evidence suggests that patients perceive their quality of life to be improved with insulin lispro when compared with regular human insulin, and that satisfaction with treatment is greater with the insulin analogue. Numerous new pharmacological approaches are under active investigation, with the aim of promoting insulin secretion, improving the action of insulin, or slowing carbohydrate absorption. With respect to continuous subcutaneous insulin infusion therapy and implantable pumps, despite that this approach is not widely utilised, it appears to bring us as close to achieving glycaemic control as is feasible with current treatment approaches. However, general application of such technology requires significant improvements in several areas, such as improvement of patency of catheter, pump failures due to early battery depletion incidents, and pump miniaturisation. Future perspective resides on insulin analogues with longer half-lives that would provide better basal insulin coverage in association with fast-acting analogues.

SummaryThe use of a placebo control group in the evaluation of a new product is today considered by most as a necessary condition of experimental drug research. Placebo response is an essential consideration in all clinical trials. If not properly controlled, incorrect and dangerous conclusion may be inferred for a product efficacy and safety profile. However, the inclusion of a placebo group in clinical trials in neuropsychiatric research raises several ethical and scientific questions. Whereas in certain indications, such as suicidal patients and severe and psychotic depression, the use of a placebo is generally not accepted, it is difficult to assess drug efficacy. This article discusses the concept of placebo in clinical trials, the occurrence of adverse events after placebo treatment and the high response rate of placebo in neuropsychiatric clinical research. The experimental methodology to adequately control all the factors involved is also analysed and discussed.

The cost of the development of a new pharmaceutical product from its conception and synthesis through to the regulatory approval process has more than quadrupled in the last 20 years. Both clinical and total development times have increased substantially. To amortize the costs incurred, the pharmaceutical industry has taken an international dimension. The incentives for pharmaceutical firms to discover and develop new drugs depend on the length of the development and regulatory review process plus the potential market size. Recent regulatory, economic and political changes may have significant implications for the future of new drug developments in Europe. The European Union industrial policy felt that there is a need for convergence in the area of pricing. It is recommended that the policy should aim to contain growth in pharmaceutical expenses by means specific to reimbursement rather than direct price controls. By encouraging doctors to prescribe and customers to use generics, competition is enhanced to bring down drug prices. More emphasis is being laid by government in educating customers to cost-awareness and cost-benefit ratios with regard to pharmaceuticals. Concerning clinical trials, European harmonization has been achieved by significant developments: the rights and integrity of the trial subjects are protected; the credibility of the data is established; and the ethical, scientific and technical quality of the trials has improved. Future European health care forecasts a whole change in the pharmaceutical business. Important issues in cost and outcome measurement should be carefully planned and considered in drug development. Due to important mergers and acquisitions, the pharmaceutical sector will consist mainly of important multinational corporations. In this way, valuable new products may be brought to the market.

Bipolar disorder is a pathological disturbance of mood, characterized by waxing and waning manic, depressive and, sometimes distinctly mixed states. A diagnosis of bipolar disorder can only be made with certainty when the manic syndrome declares itself. Most individuals who are diagnosed with this disorder will experience both poles of the illness recurrently, but depressive episodes are the commonest cause of morbidity and, indeed, of death by suicide. Twin, adoption and epidemiological studies suggest a strongly genetic aetiology. It is a genetically and phenotypically complex disorder. Thus, the genes contributing are likely to be numerous and of small effect. Individuals with bipolar disorder also display deficits on a range of neuropsychological tasks in both the acute and euthymic phases of illness and correlations between number of affective episodes experienced and task performance are commonly reported. Current self-report and observer-rated scales are optimized for unipolar depression and hence limited in their ability to accurately assess bipolar depression. The development of a specific depression rating scale will improve the assessment of bipolar depression in both research and clinical settings. It will improve the development of better treatments and interventions. Guidelines support the use of antidepressants for bipolar depression. With regard to the adverse effects of antidepressants for bipolar depression, double-blind, placebo-controlled data suggest that antidepressant monotherapy or the addition of a tricyclic antidepressant may worsen the course of bipolar disorder. Importantly, adjunctive psychotherapies add significantly (both statistically and clinically) to the efficacy of pharmacological treatment regimens. The successful management of bipolar disorder clearly demands improved recognition of bipolar disorder and effective long-term treatment for bipolar depression as well as mania.

To date, no large-scale, controlled trial comparing a serotonin-norepinephrine reuptake inhibitor and selective serotonin reuptake inhibitor with placebo for the treatment of panic disorder has been reported. This double-blind study compares the efficacy of venlafaxine extended-release (ER) and paroxetine with placebo. A total of 664 nondepressed adult outpatients who met DSM-IV criteria for panic disorder (with or without agoraphobia) were randomly assigned to 12 weeks of treatment with placebo or fixed-dose venlafaxine ER (75 mg/day or 150 mg/day), or paroxetine 40 mg/day. The primary measure was the percentage of patients free from full-symptom panic attacks, assessed with the Panic and Anticipatory Anxiety Scale (PAAS). Secondary measures included the Panic Disorder Severity Scale, Clinical Global Impressions--Severity (CGI-S) and--Improvement (CGI-I) scales; response (CGI-I rating of very much improved or much improved), remission (CGI-S rating of not at all ill or borderline ill and no PAAS full-symptom panic attacks); and measures of depression, anxiety, phobic fear and avoidance, anticipatory anxiety, functioning, and quality of life. Intent-to-treat, last observation carried forward analysis showed that mean improvement on most measures was greater with venlafaxine ER or paroxetine than with placebo. No significant differences were observed between active treatment groups. Panic-free rates at end point with active treatment ranged from 54% to 61%, compared with 35% for placebo. Approximately 75% of patients given active treatment were responders, and nearly 45% achieved remission. The placebo response rate was slightly above 55%, with remission near 25%. Adverse events were mild or moderate and similar between active treatment groups. Venlafaxine ER and paroxetine were effective and well tolerated in the treatment of panic disorder.

BackgroundVenlafaxine extended-release (ER) has proven efficacy in the treatment of anxiety symptoms in major depression, generalised anxiety disorder and social anxiety disorder.AimsTo evaluate the efficacy, safety and tolerability of venlafaxine ER in treating panic disorder.MethodAdult out-patients (n=361) with panic disorder were randomly assigned to receive venlafaxine ER (75–225 mg/day) or placebo for up to 10 weeks in a double-blind study.ResultsVenlafaxine ER was not associated with a greater proportion of patients free from full-symptom panic attacks at the finalon-therapy evaluation, but was associated with lower mean panic attack frequency and a higher proportion free from limited-symptom panic attacks, higher response and remission rates, and improvements in anticipatory anxiety, fear and avoidance. Adverse events were comparable with those of the drug in depression and anxiety disorders.ConclusionsVenlafaxine ER seems to be effective and well tolerated in the short-term treatment of panic disorder.

AD is characterized by multiple deficits including alterations to the cholinergic system (a major target in the neurotransmitter research because it is central to the cognitive changes observed in AD), the noradrenergic system, the serotonergic system and the dopaminergic system. According to the cholinergic hypothesis, the impairment of cognitive function and the behavioral disturbances that affect patients with AD are mainly due to cortical deficiencies in cholinergic neurotransmission. Deficiencies in the cholinergic system may also be involved in the formation of amyloid plaques and NFTs.

Behavioral and psychological symptoms of dementia cause premature institutionalization and significant loss of quality of life for the patient and his/her family and caregivers. An imbalance of different neurotransmitters (ACh, dopamine, noradrenaline, serotonin) has been proposed as the neurochemical correlate of these neuropsychiatric symptoms. The significant decrease in cholinergic activity may result in a relative increase in monoaminergic activities, leading to hypomanic or manic symptoms and behavior including delusions, hallucinations and physical aggression (Folstein, 1997). Conversely, AChE inhibitors have shown to be able to reduce neuropsychiatric severity (see Table 13.1).

AD and other types of dementias are associated with many problematic behaviors. Noncognitive feature is a terminology that draws the distinction between cognitive loss and the heterogeneous group of symptoms that include psychiatric symptoms such as depression, hallucinations, delusions and misidentifications. This term also includes behavioral disturbances such as aggression, agitation, pacing and eating disorders (Burns et al., 1990). An alternative expression is neuropsychiatric features (Cummings et al., 1994). The term “Behavioral and Psychological Symptoms of Dementia” (BPSD) has also been defined as “symptoms of disturbed perception, thought content, mood and behavior that frequently occur in patients with dementia” (Consensus Conference on the Behavioral Disturbances of Dementia, 1996). Noncognitive disorders can cause distress both to patients and carers. Such changes are often a determinant for institutional care. A study reported that psychotic symptoms (e.g., hallucinations and delusions) were present in about 50% of patients with dementia and disruptive behavior (e.g., physical violence, hiding things, wandering, demanding or critical behavior) in up to 70% (Rabins et al., 1982). These include hitting, yelling, grabbing people, wandering, hoarding, and repetitive gestures and questioning (Moak & Fisher, 1990; Reisberg et al., 1987). All of these problematic behaviors are often grouped together as “agitation” or “agitated behavior”.

Because functional impairment is one of the main consequences of the dementing process, patients are no longer able to engage in meaningful activities on their own. Demented patients cannot pursue hobbies because of apraxia; they cannot read because of comprehension difficulties and they cannot engage in social activities because of aphasia. Meaningful activities may improve depression, diminish agitation, apathy, insomnia and repetitive vocalization and should be attempted. Meaningful activities are important at all stages of dementing illnesses. Individuals with advanced dementia need stimulation with appropriate activities because few, if any, patients with AD progress to the persistent vegetative state (Volicer et al., 1997).

Since the ACh deficit associated with AD was recognized in the mid-1970s, there has been a systematic attempt to increase CNS cholinergic activity by pharmacological manipulations. The main classes of drugs tested so far include ACh precursors, releasing agents, cholinesterase inhibitors (CI) and muscarinic agonists. The expectations were that cholinergic enhancement would improve symptoms of AD in a way similar to dopamine enhancement in Parkinson’s disease.

The most important cognitive deficit of AD is the progressive loss of memory that is manifested according to the traditional classification in both STM and LTM tasks (see Tables 8.1, 8.2 and 8.3). The earliest and most prominent symptom in AD is a profound impairment in the ability to acquire and remember new information whether tested by recall or recognition (Grady et al., 1988; Welsh et al., 1991). Many patients have purely episodic memory impairment for a number of years (Perry & Hodges, 2000; Perry et al., 2000). Semantic memory, the database of conceptual knowledge that gives meaning to sensory experience, is eventually affected in AD, but early in the disease patients show mild and variable impairment of semantic memory. Written language deficits are frequently noted and occur at early beginning of the disease (Eustache & Lambert, 1996). They initially take the form of a lexical agraphia: the characteristic symptom is the production of errors so called “de regulation” (of regulation) occurring during the writing of words with irregular orthography (e.g. femme > fame). On the contrary, deficits of phonological type often appear with the progression of the dementia.

In clinical practice, the behavioral disturbances seen in patients with dementia are helpful in determining disease severity and the need for support care. In patients with AD, the early appearance of behavioral symptoms is associated with faster disease progression. The first neuropsychological dysfunction in AD is described as a loss of attention capacity, followed by loss of language and visuospatial function (Grady et al., 1988). Behavioral complications of dementing illness are common, adversely affecting the quality of lives of patients and caregivers. They create stress for caregivers, complicate patient management and often precipitate institutionalization. About 70-90% of patients with dementia exhibit behavioral and psychological symptoms at some time during the course of the disease. There has been growing interest in the detection and quantification of the emotional, behavioral, ideational, perceptual and vegetative symptoms that accompany and complicate the lives of persons with AD and their caregivers. The availability of scales to detect and quantify these aspects of the disease is important to clinical investigators seeking effective means of treating these symptoms. Reliable quantification of behavior is desirable to facilitate documentation of symptoms, provide a tool for follow-up of behavioral changes over time and enable researchers to measure the effects of behavioral and pharmacological intervention.

The hypothesis that a cholinergic deficit might be responsible for memory impairment was based on studies showing learning and memory deficits in animals and humans whose cholinergic system was blocked by atropine or scopolamine (Drachman, 1977). Confirmation was sought by animal investigations in which the forebrain cholinergic nuclei were destroyed, initially by electrolytic lesions, then by excitotoxins and finally by the selective immunotoxins 192 IgG-saporin (Wenk et al., 1994). Intracerebroventricular (i.c.v.) injection of 192 Ig-G-saporin brings about a widespread degeneration of cholinergic neurons including the nucleus basalis of Meynert and the septum (Lin et al., 1999). The reversion of the learning and memory deficits induced by nucleus basalis of Meynert lesions has become a classical preclinical test for the screening of drugs aimed to correct the cholinergic hypo-function in AD (see Pepeu, 2000).

Memory is a theoretical construct that may explain current behavior by reference to events that have happened or will happen in the future. Memory may be conceived as a complex, dynamic, recategorising and interactive process based on actual sensory-motor experiences and manifests itself in the behavior of an organism. Repetition in learning is a prerequisite for the formation of accurate and long-lasting memory. Practice is most effective when widely distributed over time, rather than when closely spaced or massed. But even after efficient learning, most memories dissipate with time unless frequently used (Spear, 1978; Spear & Riccio, 1994). Memory always has a subjective and an objective side. The subjective side is observed by the individual’s history (developmental perspective). The objective side is noted by the neural patterns generated by the sensory-motor interactions with the environment. It has been well established by many memory researchers that memory is not a unitary function. This notion is supported by evidence that different brain lesions in patients produce highly specific changes in some aspects of memory functions while sparing other ones. Research has attempted to delineate patterns of impaired and spared memory functions in order to assess whether there is a particular class of processing system that is not functioning while other systems function normally.

AD is a multifactorial disease implicating interactions between environmental and genetic factors. However, there are various genetic defects that may predispose an individual to AD. AD cases can be divided into familial and sporadic cases as well as early onset (EOAD: 65 years) (see Table 4.1). Familial AD (FAD) cases are rare, comprising only 5-10% of all cases. Mutations in several genes have been described as causes of AD: the PS1 gene in chromosome 14, the PS2 gene in chromosome 1, and the APP in chromosome 21 (Sherrington et al., 1995; Levy-Lahad et al., 1995; Goate et al., 1991). All known mutations that predispose a person to EOAD either increase the overall level of Aβ production or increase the ratio of Aβ42 to Aβ40 (Suzuki et al., 1994; Borchelt et al., 1996).

Aging of the brain is accompanied by multiple changes in morphology and functional variations at the cellular and molecular levels of nerve cells. Neuritic plaques, one of the two diagnostic brain lesions observed in Alzheimer’s original patient, are microscopic foci of extracellular amyloid deposition. They are associated with axonal and dendritic injury, and are generally found in large numbers in the limbic and association cortices (Dickson, 1997).

GAD is defined as anxiety, tension or worry associated with a considerable number of patients displaying a mix of somatic and psychological symptoms. The diagnostic definitions of GAD in various manuals, including ICD-10 and DSM-III/IV, differ in quality, number of symptoms, time frames and exclusion criteria. Consequently, lifetime prevalence rates vary between 1.2 and 6.4% in epidemiological surveys (Wittchen et al., 1994). Although the diagnostic reliability of GAD is comparatively low, the features constituting the diagnostic criteria have been noted to be reliable (Di Nardo et al., 1993). A study that compared the distribution of somatic symptoms associated with GAD in patients with “pure” GAD and patients with GAD plus comorbid current or lifetime psychiatric diagnoses showed that GAD is a distinct disorder that is relatively consistent in presentation in patients with or without other psychiatric disorders (Brawman-Mintzer et al., 1994). The hypothesis of the existence of distinct subtypes of GAD, i.e. a “pure” GAD and a “secondary” type with comorbid disorder, representing possibly a prodromal/residual state or an epiphenomenon associated with another disorder, was therefore not confirmed.

OCD is characterised by recurrent, unpleasant thoughts which enter consciousness against the will of the individual, termed obsessions, and repetitive, unwanted behaviours, which may be ritualistic, termed compulsions, that lead to severe impairment in daily functioning. One of the most common compulsions is cleaning. Some individuals concerned about contamination will spend hours showering or bathing, others will wash their hands almost constantly, and some will spend hours and hours of each day cleaning their home. In addition to cleaning there are a number of other compulsions including checking (e.g., individuals may check hundreds of times if all doors at home are locked), repeating (e.g., some people may wish to ease anxiety by repeating a name or phrase over and over), slowness (being overly meticulous and tidy and spending hours organising and arranging objects and possessions) and fear of contamination (e.g., a person may devote hours of the day to washing their hands and avoids any social contact with others due to the fear of contamination).

The symptoms of “anxiety” are listed under two headings. Subjective ones (i.e. those felt as “psychological” experiences) include fear, emotional worries, feelings of terror, depersonalisation etc., and occasionally mental acts such as obsession-like thoughts concerning the safety of others, fear of dying etc. On the other hand, the “objective” symptoms of anxiety (also called “somatic” and later on “anxiety-equivalents”) include abdominal pain, nausea, vertigo, dizziness, palpitations, dry mouth, hot flushes, hyperventilation, breathlessness, headache, restless legs, and other bodily experiences sometimes indistinguishable from complaints caused by physical disease. At the beginning of the 19th century, Landre-Beauvais (1813) defined “anxiete” as “a certain malaise, restlessness, excessive agitation” suggesting that these states may accompany “acute” and “chronic” diseases. With this approach, anxiety becomes a syndrome with both subjective and somatic components, and which can accompany diverse diseases.

Very little is known about the biological basis of anxiety disorder. Variance in personality traits, including those related to anxiety, is thought to be generated by a complex interaction of environmental and experiential factors with a number of gene products involving distinct brain systems such as the midbrain raphe serotonin (5-hydroxytryptamine, 5-HT) system (Loehlin, 1989; Plomin et al., 1994). Although twin studies have indicated that individual variation in measures of anxiety-related personality traits is 40-60% heritable, none of the relevant genes has yet been identified (Loehlin, 1989).

Because anxiety is a concept that describes a human subjective state, its absolute reproduction in animals is an impossible target. Since animals cannot tell us about the experience of anxiety and fear, a rich source of information that is readily obtained from humans with anxiety disorders may be missed. Therefore, it can only be modelled in animals. A model is an artificial representation of a disease or some aspects of it. Models are often evaluated on a continuum of similarity to the disease (Howard et al., 1989). In theory, the ideal model may reproduce all the features of the phenomenon under investigation and as such would be an exact reproduction rather than a model. In many instances in psychopharmacological research, a model is understood to be a screening method, validated at the standard drug correlational level. Therefore, an animal model of anxiety may be considered as an approach that registers positive for clinically proven anxiolytics and negative for drugs that are thought to be nonanxiolytic in that they usually do not relieve the symptoms of anxiety.

Anxiety disorders tend to be chronic conditions. Women are more prone than men to essentially all anxiety disorders (Bland et al., 1988; Kessler et al., 1994; Offord et al., 1996; Robins & Regier, 1991). Epidemiological studies suggest that women have a 2-to 3-fold increase in the occurrence of PD, PTSD and GAD. Fluctuations in oestrogen and progesterone levels can substantially influence the severity and course of anxiety disorders. Future investigations that focus on gender differences may provide valuable information for effective treatment strategies for women with anxiety disorders.

Single nucleotide polymorphisms (SNPs) represent a valuable resource for the genetic analysis of cancer and other illnesses. SNPs are single-letter variations between people or individuals that determine susceptibility to diseases and the ability to combat illness and therefore data on SNP-based genetic variations are being collected. These markers can be used in a variety of ways to investigate the genetic underpinnings of disease. In gene-based studies, the correlation between allelic variants of genes of interest and particular disease states is assessed. A significant feature of this approach to sequence the human genome is the use of genetic material from both men and women of various ethnic backgrounds. An extensive collection of SNP markers might enable entire molecular pathways regulating cell metabolism, growth or differentiation to be analysed using this approach. The development of detailed SNP maps of the human genome, coupled with high-throughput genotyping technologies, might permit complex genetic traits to be unravelled over the next few years 1xSee all References1. This approach should allow the development of a database for studying the genetic variations between individuals in parallel to deciphering the genome sequence.Finishing the sequencing, however, is nothing more than the creation of the scientific infrastructure that will enable the next stage of the biotechnology revolution. Although identifying 80 000–100 000 human genes is conceptually within the reach of the research community, understanding the functions of all of the genes and the intricacies involved therein are daunting tasks that will keep the scientific community involved for many years to come. The sooner the sequencing is completed and the task of function determination started, the better it will be for us to reap the fruits of the progress made in biotechnology.Gene therapy offers society the potential of curing many diseases, including inherited diseases, as well as heart disease and cancer. It offers the potential to deal with the primary causes and could eliminate many conventional therapies based on small molecules and proteins, some of which have serious side effects or pose additional risk to the patient. Unfortunately, genetic therapeutics has come into the limelight because of the unfortunate death of Jesse Gelsinger at the University of Pennsylvania in September 1999. The public opinion generated by this tragedy has opened the field of genetic engineering to criticism. Another appalling incident in February 2000, in which the FDA revealed that some children suffering from neuroblastoma might have received injections of HIV and hepatitis C virus from a preparation that was improperly prepared and tested, made things worse. However, subsequent testing confirmed that the product was safe by existing standards.The rapid accumulation of genetic information generated by the Human Genome Project and related research has heightened public awareness of genetic issues. Education in genome science is needed at all levels in our society so that individuals can make well-informed decisions related to public policy and issues such as genetic testing. To be most successful, genome education programs will require the collaborative efforts of science teachers, genome researchers, ethicists and genetic counsellors.Following recent research, it seems clear that comparative genomics has been identified as one of the most important steps after individual genome sequence analysis. Promoter modeling allows this to be extended into regions where conventional sequence alignments miss most or even all of the conserved features, such as binding sites, that can be too divergent to be picked up by direct sequence alignment. Looking to the future, the gene therapy laboratory will probably resemble the protein laboratory in most respects. The use of the PCR will certainly grow in importance because it differentiates between active drug and most contaminants. Hybridization assays for DNA will also find favor because they are rapid and easy to use. Hopefully, the potential problem of how to interpret a nonzero background will soon be solved. All in all, the gene therapy support and regulatory laboratories should not be that much different from that which exists today. New techniques will certainly be developed and most will probably be evolutionary, rather than revolutionary.

Genomics, particularly high-throughput sequencing and characterization of expressed human genes, has created new opportunities for drug discovery. Knowledge of all the human genes and their functions may allow effective preventive measures, and change drug research strategy and drug discovery development processes. Pharmacogenomics is the application of genomic technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and on the market. It applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients. The possibility of defining patient populations genetically may improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology. Ethical questions need to be addressed and guidelines established for the use of genomics in clinical research and clinical medicine. Significant achievements are possible with an interdisciplinary approach that includes genetic, technological and therapeutic measures.

Alzheimer disease (AD) involves neuronal degeneration with impaired cholinergic transmission in the cerebral cortex and hippocampus in areas of the brain particularly associated with memory and higher intellectual functioning. Other neurotransmitter deficits also occur, but the mechanisms underlying the widespread impairment of synaptic functions remain uncertain. Research on the molecular basis of AD has elucidated a pathogenic pathway from which a range of rational pharmacological interventions has emerged. Although at least 3 cholinesterase inhibitors (tacrine hydrochloride, donepezil, and rivastigmine tartrate) are now available and provide patients with modest relief, the most promising strategy involves approaches to retarding, halting, or preventing the formation or accumulation of beta-amyloid (Abeta) plaques. Estrogen is believed to have antioxidant or other anti-Abeta effects, as hormonal replacement therapy in women with menopause is associated with a reduced risk or delayed onset of AD. The association between nonsteroidal anti-inflammatory drugs and a reduced risk of AD has not yet been confirmed, but these agents may protect the brain from the reactive glial and microglial responses associated with Abeta deposition. Also, recent studies suggested that antioxidants, such as vitamin E taken alone or in combination with selegiline hydrochloride, can delay the progression of AD. Despite these encouraging results, no current therapy has been shown to halt or reverse the underlying disease process. The proof of the principle that anti-Abeta drugs will work in the transgenic models of AD is eagerly awaited with the expectation that they will eventually prove successful in humans.

There are two families of dopamine (DA) receptors, called D1 and D2, respectively. The D1 family consists of D1- and D5-receptor subtypes and the D2 family consists of D2-, D3-, and D4-receptor subtypes. The amino acid sequences of these receptors show that they all belong to a large superfamily of receptors with seven transmembrane domains, which are coupled to their intracellular signal transduction systems by G-proteins. The implications of DA receptors in neuropsychiatry and cardiovascular and renal diseases are discussed. Neuropsychiatry indications include Parkinson's disease, schizophrenia, migraine, drug dependence, mania and depression, and Gilles de la Tourette syndrome. The underlying dysfunction of dopaminergic systems and the potential benefits of dopaminergic therapy in these different indications are critically examined. With respect to the pharmacological treatment of Parkinson's disease, a range of DA agonists are in various stages of preclinical and clinical development. D2-receptor agonist activity is predominant in most effective antiparkinsonian DA agonists. However, in practice, it is difficult to treat patients for several years with DA agonists alone; therapeutic benefit is not sustained. Rather, the use of a combination of DA agonists and levodopa is considered preferable. Reports of the efficacy of DA partial agonists await confirmation, and recent clinical investigations also suggest the potential of D1 receptor agonists as antiparkinson drugs. Regarding migraine pathogenesis, clinical and pharmacological evidence suggests that DA is involved in this disorder. Most prodromal and accompanying symptoms may be related to dopaminergic activation. Several drugs acting on DA receptors are effective in migraine treatment. Furthermore, migraine patients show a higher incidence of dopaminergic symptoms following acute DA agonist administration, when compared with normal controls. In cardiology, the therapeutic benefits of DA agonists are noted in the treatment of heart failure. Low doses of DA are widely used for its specific dopaminergic effects on renal function, which are suggested to be beneficial, and for its alpha- and beta-adrenergic-mediated responses that occur with higher doses. However, studies have been unable to demonstrate that DA can prevent acute renal failure or reduce mortality. It appears that the significant progress that is being made in the molecular understanding of DA receptors will continue to have a tremendous impact in the pharmacological treatment of neuropsychiatric, cardiovascular, and renal diseases.

The hypothesis that lithium is the most appropriate and efficacious pharmacological treatment in the therapy of manic-depressive illness was examined in a meta-analysis. The efficacy of lithium was compared with that of the antiepileptics, carbamazepine and valproic acid. Data sources include the Medline database and relevant references from articles. Only randomised controlled clinical trials with a double-blind assessment of outcomes were included. Lithium levels were required to be within the therapeutic range of 0.4-1.5 mmol/l. The effect sizes were measured by the odds ratio using the Mantel-Haenszel method. No significant difference was observed between the treatment effect of the 3 drugs compared. While the efficacy of the 3 treatments was identical, there is a general tendency in favour of the antiepileptics in the treatment of manic depression with regard to adverse events and treatment tolerance. The impact and importance of this study seriously question the relevance of today's practice of prescribing lithium in the acute management of manic-depressive illness.

From Genome to Therapy: Integrating new technologies with drug developmentedited by Gregory R. Bock, Dalia Cohen and Jamie A. Goode,John Wiley & Sons Ltd, 2000,£75.00 (hbk) (174 pages)ISBN 0 471 62744 5The dogma of genomics is that DNA leads to RNA, which leads to proteins that provide function. Thus, to fundamentally change things, the gene might be the place to start. Gene therapy entails development of new technology along the entire product development process. This book covers the presentations delivered during the symposium ‘From genome to therapy’ that was held at the Hotel Europe, Basel, Switzerland, 22–24 June 1999.The first chapter includes an introduction by Craig Venter. Venter emphasizes that in recent years there has been a tremendous number of genes discovered and that we are in the early part of an exponential growth phase in which genomes of all types are being deciphered. The original aim of the genome project was to decode the genomes of only five organisms (Eschericia coli, Saccharomyces cerevisiae, Drosophila, mouse and human). A challenge that now faces all researchers is that roughly half of the genes in each species that have been sequenced are completely unknown genes that appear to be species specific. Another challenging issue is the central dogma that one gene leads to a transcript that leads to one protein with a single function. However, current evidence suggests that this central dogma is more complicated; one gene product can probably have cellular interactions that result in a wide variety of outcomes. Later on in the book, Venter discusses the genomic impact on pharmaceutical development and emphasizes that, in the near future, the development of important new pharmaceutical compounds will undergo considerable changes. Target discovery, lead compound identifications, pharmaco-toxicology and clinical studies will probably merge with the science of bioinformatics into a powerful new approach for the discovery of effective new medicines. He foresees a paradigm of ‘cyberpharmaceutical’ testing that will help to speed up the selection of promising new drugs, compounds that are likely to exhibit toxicity will be eliminated and the costs and risks associated with the current approaches of drug development will be decreased.A chapter by William Efcavitch presents the current state of automated DNA sequencing technology and additional technical advances that will continue to decrease and increase throughput of automated DNA sequencing. He points out that the demands for the sequencing of the human genome to be completed, coupled with the increased use of genomics in the pharmaceutical discovery process, has led to the recent development and introduction-scale DNA analysers based on capillary electrophoresis. Although electrophoretic-based DNA sequencing technology has been in place for some time, continued advances in basic separation science, detection methodologies, automation and sample preparation, promise to keep this methodology in the forefront of genetic analysis.In an account on large-scale experimental approaches, Matthias Mann suggests that mass spectrometry will resurrect protein-based approaches in functional genomics and Allen Roses welcomes the era of susceptibility gene identification and ‘right medicine for right patient’ therapeutics.The pharmaceutical industry perspective of genome therapy is outlined in a chapter by Paul Herling. He emphasizes that functional genomics will impact pharmaceutical R&D beyond discovery research. It will allow the profiling of efficacy, as well as of the side effects associated with novel and existing medicines, which will lead to ‘personalized’ medical needs. Research in the pharmaceutical industry will be targeted towards disease-relevant targets and will provide a starting point for the discovery of what causes disease and therapies that modify it. Peter Goodfellow then goes on to describe the impact of genomics on drug research and emphasizes that by increasing the spectrum of available targets for drug discovery, functional genomics will improve the chances of producing novel pharmaceutical products.The ethical issues raised by the application of genetic therapy are described in a chapter by David Magnus. Although short-term problems concern mostly the ethical impact in diagnostics, with the primary therapies being prenatal diagnosis and abortion, long-term issues might be slightly different. Given that technology will probably permit the creation of artificial chromosomes ‘from scratch’ within 10–20 years, the potential to design synthesised life forms will give rise to a new era of biotechnology. There will be concerns over ownership and control of living things and of genetic material. The consideration of the legal and ethical aspects of patenting genes and gene therapy led Joseph Strauss to conclude that although for many groups and regulatory bodies resistance to gene therapy is primarily based on the principle that neither patents on any life forms or on discoveries should be allowed, the pharmaceutical industry is more concerned that patents issued on expressed sequence tags (ESTs) and single polymorphisms (SNPs) could hamper the development of new therapies.Finally, although the book is a little out of date owing to the tremendous explosion of recent data and progress in this research area, it is nevertheless easy to read and includes many interesting discussions about the broad field of genomics with many active researchers and experts cited.