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The future with amphetamines

Leslie Iversen

in Speed, Ecstasy, Ritalin: The Science of Amphetamines

The previous chapters have reviewed the various uses and abuses of amphetamines in different societies. These man-made chemicals had a great impact on ... More

The previous chapters have reviewed the various uses and abuses of amphetamines in different societies. These man-made chemicals had a great impact on life in the 20th century and seem set to continue as major players — for good as well as evil. This concluding chapter attempts to put some perspective on the use and abuse of these drugs and attempts some predictions of future trends. It also explores the medical uses of amphetamines, particularly in cases of ADHD; the continuing spread of illicit amphetamine abuse; and the possible treatments for amphetamine addiction.Less

Amphetamine psychosis:: how research on amphetamines provided new insights into the brain mechanisms underlying schizophrenia

Leslie Iversen

in Speed, Ecstasy, Ritalin: The Science of Amphetamines

The resemblance between amphetamine-induced psychosis and some forms of schizophrenia generated much interest in the research community. New lines of ... More

The resemblance between amphetamine-induced psychosis and some forms of schizophrenia generated much interest in the research community. New lines of research sought to examine how close the parallels were and to probe their underlying neurochemical and neuropharmacological bases. This work was of great importance in supporting the ‘dopamine hypothesis’ of schizophrenia and providing insight into the mechanism of action of the anti-psychotic drugs used to treat schizophrenia as dopamine antagonists. Although no short-term drug-induced effects can ever accurately mimic the symptoms of complex and chronic psychosis, amphetamine comes closer than any other. Research on amphetamine in animals and in human subjects has contributed importantly to these ideas.Less

Poisoning and Pharmacology

Nigel Lane, Louise Powter, and Sam Patel (eds)

in Best of Five MCQs for the Acute Medicine SCE

Stimulants and Dopamine Augmenters

Chiadi U. Onyike

in Psychiatric Aspects of Neurologic Diseases: Practical approaches to patient care

Stimulants are typically prescribed for their positive effects on mood, motivation, alertness, arousal, and energy. They are believed to exert their ... More

Stimulants are typically prescribed for their positive effects on mood, motivation, alertness, arousal, and energy. They are believed to exert their pharmacologic effects by increasing synaptic release of endogenous catecholamines (norepinephrine and dopamine) while simultaneously blocking catecholamine reuptake at the nerve terminals. Themost commonly used ‘‘traditional’’ agents are methylphenidate and dextroamphetamine. Methylphenidate reaches peak blood levels in 1 to 3 hours and has an elimination half-life of 2 to 3 hours. Dextroamphetamine reaches peak levels in 2 to 4 hours and has an elimination half-life of 3 to 6 hours. Controlled-release formulations are available, allowing for dosing once daily. Dextroamphetamine is excreted primarily in the urine in unchanged form, whereas methylphenidate is excreted mainly as ritalinic acid. The newer generation stimulant modafinil has been marketed in the United States since 1998. Initially used in the treatment of narcolepsy, it is now prescribed for a wider range of conditions because of its positive effects on wakefulness, vigilance, cognitive performance, and mood. Its pharmacologic effects are thought to result primarily from the stimulation of wakefulness-promoting orexinergic neurons in the anterior hypothalamus. Inhibition of norepinephrine reuptake in the ventrolateral preoptic nucleus and of dopamine reuptake (by binding to the transporter) may contribute to its action. Modafinil is administered orally, achieves peak plasma concentrations in 2 to 4 hours, and has an elimination half-life of 12 to 15 hours. It is 90% metabolized in the liver, and its metabolites are excreted in the urine. The ergot alkaloids bromocriptine and pergolide are familiar to most neurologists in their use in the treatment of Parkinson’s disease (PD) and migraine headache. These dopamine receptor agonists are also used in neuropsychiatry in the treatment of apathetic states in patients recovering from brain trauma, cerebral anoxia, and strokes. Amantadine is another familiar agent used in the treatment of PD and drug-induced parkinsonism. In addition to other effects in the central nervous system (CNS), amantadine facilitates dopamine release and inhibits its reuptake. It thus has modest ‘‘stimulant-like’’ effects useful in the treatment of executive dysfunction syndromes, particularly in patients with dementia. Bupropion is a dopamine and norepinephrine reuptake inhibitor. It usually is prescribed as a ‘‘nonsedating’’ antidepressant, but its potentiation of catecholamine neurotransmission results in modest stimulant-like clinical effects. Less

Introduction

Leslie Iversen

in Speed, Ecstasy, Ritalin: The Science of Amphetamines

Amphetamines come in many different forms and have powerful effects for good and evil. An epidemic of methamphetamine abuse is sweeping through the USA ... More

Amphetamines come in many different forms and have powerful effects for good and evil. An epidemic of methamphetamine abuse is sweeping through the USA and Southeast Asia — from Hawaii, where the epidemic started in the 1980s, and from Thailand. Meanwhile another amphetamine-like chemical, methylphenidate (Ritalin) has proved popular for the treatment of children, and more recently adults, with attention deficit hyperactivity disorder (ADHD) on both sides of the Atlantic. This book seeks to review the positive and negative aspects of amphetamines — man-made chemicals which had a great impact on the 20th century and continue to do so in the new millennium.Less

What are amphetamines and how do they work in the brain?

Leslie Iversen

in Speed, Ecstasy, Ritalin: The Science of Amphetamines

This chapter discusses the chemistry of amphetamines and their effects on the brain. Amphetamines are easily administered by a variety of routes and they ... More

This chapter discusses the chemistry of amphetamines and their effects on the brain. Amphetamines are easily administered by a variety of routes and they penetrate readily and rapidly into the central nervous system (CNS). They act by stimulating the release of natural neurotransmitters. In peripheral tissues, amphetamine stimulates the release of norepinephrine from the nerve endings of the ‘sympathetic nervous system’ which controls a variety of peripheral functions. Because of its ability to stimulate functions normally controlled by the sympathetic nervous system, amphetamine has long been recognised as a ‘sympathomimetic amine’. This chapter also discusses the effects of amphetamines on human mood, cognitive performance, sexual function, and the stereotyped behaviour in human amphetamine users.Less

Illicit amphetamine use around the world

Leslie Iversen

in Speed, Ecstasy, Ritalin: The Science of Amphetamines

A United Nations report (United Nations 2003) estimated a worldwide total of 34 million people who regularly abuse amphetamine-like stimulants and 8 ... More

A United Nations report (United Nations 2003) estimated a worldwide total of 34 million people who regularly abuse amphetamine-like stimulants and 8 million who use ecstasy. This exceeds the number of heroin and cocaine abusers combined. D-Amphetamine and D-methamphetamine are among the most widely used of all illicit drugs, ranking second in popularity only to cannabis in many countries. It is now generally recognized that amphetamines are drugs of addiction. This chapter reviews the evidence for this and explores the underlying brain mechanisms. It also reviews the social history of amphetamine abuse in various parts of the world.Less

How dangerous are the amphetamines?

Leslie Iversen

in Speed, Ecstasy, Ritalin: The Science of Amphetamines

All drugs, even such apparently innocuous ones as aspirin, carry some health risks. But how dangerous are the amphetamines? Can an overdose kill someone? ... More

All drugs, even such apparently innocuous ones as aspirin, carry some health risks. But how dangerous are the amphetamines? Can an overdose kill someone? Does amphetamine abuse cause damage to the health and social lives of the users and those around them? Are there any long-term irreversible adverse effects of chronic use? This chapter attempts to answer some of these questions and reviews the extensive literature on the neurotoxicity of amphetamines studied in animal experiments. Overall, the use of high-dose amphetamine is associated with an alarming series of adverse risks for both the user and those around him.Less

How is Schizophrenia Diagnosed?

Stephen J. Glatt, Stephen V. Faraone, and Ming T. Tsuang

in Schizophrenia

The diagnosis of schizophrenia cannot be made based on the results of an ob­jective diagnostic test or laboratory measure, though we and others are working towards ... More

The diagnosis of schizophrenia cannot be made based on the results of an ob­jective diagnostic test or laboratory measure, though we and others are working towards this. Instead, clinicians diagnose schizophrenia based on behaviour and psychopathology (including the symptoms described in the previous chapter). These require the subjective interpretation of clinicians, but they can be as­sessed reliably. The definitions of major mental illnesses used by clinicians are presented in the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association (in the United States) and the World Health Organization’s International Classification of Diseases (ICD) in other countries. These def­initions are updated from time to time to reflect gains in knowledge, or to reflect modern thinking on the similarities and differences between certain disorders. From one edition to the next, some diagnoses are revised, some are added, and some vanish altogether, only to be replaced or absorbed under other diagnoses. The diagnostic criteria for schizophrenia as defined by the most recent version of the DSM (DSM- 5) include the presence of two or more of the following symptoms: delusions, hallucinations, disorganized speech, disorganized or cata­tonic behaviour, and negative symptoms. At least one of the two must be delu­sions, hallucinations, or disorganized speech, while the second symptom type required for diagnosis could be any of the remaining four criteria. The require­ment of delusions, hallucinations, or disorganized speech maintains the resem­blance of the modern- day diagnosis to that first described by the clinician Emil Kraepelin over a century ago. Kraepelin’s discovery that schizophrenia is marked by a chronic and gradually worsening course is seen in modern- day criteria as well. A DSM-5 diagnosis of schizophrenia requires continuous signs of illness for at least 6 months, during which the individual must show at least 1 month of active symptoms (less if well treated). The diagnosis also requires social or work deterioration over a signifi­cant amount of time. Lastly, the diagnosis requires that the observed symptoms are not due to some other medical condition, including other psychiatric disorders such as bipolar disorder or major depressive disorder. Less

Psychiatry of older adults

Rebecca McKnight, Jonathan Price, and John Geddes

in Psychiatry

The provision of mental health services for older adults faces two main challenges: … 1 The world population is ageing, leading to increased numbers of ... More

The provision of mental health services for older adults faces two main challenges: … 1 The world population is ageing, leading to increased numbers of elderly patients (Fig. 18.1). 2 These patients are more likely to present with multiple, complex co- morbidities which must be managed alongside acute or chronic psychiatric problems…. To provide effective care, services must combine treatment for mental, physical, and social needs of older people. The multidisciplinary team is key to delivering this, often in specialized environments such as a day centre programme. A huge number of physical, psychological, and social changes occur within the normal process of ageing. A basic understanding of these is necessary in order to identify those individuals in whom there is path­ology. Covering theories behind the ageing process is outside the scope of this text, but some references are given on p. 220. The following changes are seen in the brain during normal ageing: … ● The weight of the brain decreases by 5– 20 per cent between 70 and 90 years, with a compensatory increase in ventricular size. ● There is neuronal loss, especially in the hippocampus, cortex, substantia nigra, and cerebellum. ● Senile plaques are found in the neocortex, amygdala, and hippocampus. ● Tau proteins form neurofibrillary tangles, found normally only in the hippocampus. ● Lewy bodies are seen in the substantia nigra. ● Ischaemic lesions (reduced blood flow, lacunar infarcts) are seen in 50 per cent of normal people over 65 years…. From mid life there is a decline in intellectual func­tions, as measured with standard intelligence tests, together with deterioration of short- term memory and slowness. IQ peaks at about 25 years, remains stable until 60– 70 years, and then declines. Problem- solving reduces after about age 60. There may be alterations in personality and attitudes, such as increasing cautiousness, rigidity, and ‘disengagement’ from the outside world. Later life presents a series of major changes. Many individuals retire, lose partners, lose their physical health, and are forced to live on much lower incomes and in poorer- quality housing than younger people. These are difficult transitions which may predispose to mental illness. The majority of older people remain living at home: half with a partner, and 10 per cent with other family members. Those who live alone may be­come isolated and lonely. Less

Mood disorders

Rebecca McKnight, Jonathan Price, and John Geddes

in Psychiatry

Variations in mood are part of normal experience; we all have our ‘good’ and ‘bad’ days and different ways of managing these. Sadness is a natural ... More

Variations in mood are part of normal experience; we all have our ‘good’ and ‘bad’ days and different ways of managing these. Sadness is a natural re­sponse to loss, adversity, stress, or other negative life experiences and is not necessarily abnormal. The main difference between normal sadness and a mood disorder is that normal sadness is usually a temporary state strongly relating to the person’s current situation, whereas mood disorder is a more persistent pervasive change in mood which affects social and occupational functioning. Primary mood (or ‘affective’) disorders are very common, and are also seen in most other psychiatric disorders or co-morbid to a physical illness. The distribution of mood variation in the general population is probably continuous, producing a spec­trum of severity (see Fig. 21.1). As with all psychiatric disorders, classification is descriptive and based on clinical characteristics. The most useful current approach to classification is based on the clinical course. Fundamental elements of this approach include: … ● classifying an illness as a single episode, recurrent, or persistent; ● distinguishing between people who have only low mood (unipolar depression) and those who also have elated mood (bipolar disorder); ● classifying episodes of illness according to severity: depressive episodes are mild, moderate, or severe; elated mood is hypomanic or manic (Table 21.1). … The classification includes two categories for less severe and more chronic illnesses: … ● Dysthymia: chronic mildly low mood which lasts at least several years but does not meet criteria for a recurrent depressive disorder. ● Cyclothymia: chronic instability of mood with periods of mild depressive and elation, none of which are severe enough to meet criteria for bipolar disorder or recurrent depressive disorder. It is often seen in relatives of those who have bipolar disorder, and some patients may eventually meet criteria for bipolar disorder themselves. The prevalence of mood disorders is hard to accurately ascertain, as many patients with low mood do not seek professional help. This is especially common in men. However, data from research studies (which tend to use structured diagnostic criteria) and large national sur­veys (self- report) give very similar results, outlined in Table 21.2. Bipolar disorder epidemiology is well cap­tured, as patients tend to seek help and the diagnostic criteria are well defined. Less

Schizophrenia and related psychotic disorders

Rebecca McKnight, Jonathan Price, and John Geddes

in Psychiatry

Schizophrenia and related disorders are a group of conditions characterized by psychotic symptoms which lead to impairments in thinking, feelings, ... More

Schizophrenia and related disorders are a group of conditions characterized by psychotic symptoms which lead to impairments in thinking, feelings, be­haviour, and social interactions. There is a spectrum of severity. In schizophrenia, the patient suffers from both psychotic symptoms and functional impairment. In delusional disorders, the patient experiences de­lusions, but there is no evidence of hallucinations and their functional level may remain normal. Schizophrenia can be a particularly disabling illness because its course, although variable, is frequently chronic and relapsing. The care of patients with schizo­phrenia places a considerable burden on all carers, from the patient’s family through to the health and so­cial services. GPs may have only a few patients with chronic schizophrenia on their lists but the severity of their problems and the needs of their families will make these patients important. This chapter aims to provide sufficient infor­mation for the reader to be able to recognize the basic symptoms of schizophrenia and related dis­orders and to be aware of the main approaches to treatment. As the clinical presentation and outcome of the dis­order vary, schizophrenia can be a confusing illness to understand. It is best to start by considering simplified descriptions of two common presenta­tions: (1) the acute syndrome, and (2) the chronic syndrome. It is then easier to understand the core features as well as the diversity of schizophrenia. In the acute syndrome, the patient gains symptoms; they start to have unusual experiences or thoughts they did not previously, and act in bizarre or atypical ways. This is in contrast to the contrast to the chronic syndrome, in which there is a loss of function— the negative symptoms. The positive symptoms of schizophrenia may appear within a few days, or more insidiously over a period of weeks. A typical presentation is described in Case study box 22.1, and symptoms outlined in Table 22.1. It is not necessary for the patient to have all of these symptoms; they usually have a selection which may change over time. Less

Anxiety and obsessional disorders

Rebecca McKnight, Jonathan Price, and John Geddes

in Psychiatry

In the community, the term ‘anxiety’ is frequently as­sociated with a stressful Western lifestyle and thought of as a modern phenomenon— but this is far ... More

In the community, the term ‘anxiety’ is frequently as­sociated with a stressful Western lifestyle and thought of as a modern phenomenon— but this is far from the case. Anxiety disorders were clearly described as early as the writings of Hippocrates, and have been preva­lent in literary characterization to the present. Anxiety disorders are the most common type of psychiatric disorder, with one in three people experiencing them during a lifetime. They are characterized by marked, persistent mental and physical symptoms of anxiety, that are not secondary to another disorder and that impact negatively upon the sufferer’s life. Anxiety dis­orders may be primary psychiatric conditions, or a sec­ondary response to the stress associated with physical illness and its treatment. Many people with anxiety disorders never seek medical attention, but these are commonly seen conditions in both primary and sec­ondary care, and they may present with either mental or physical complaints. Obsessive– compulsive disorder is also considered in this chapter. Its relationship to anxiety disorders is uncertain— classification systems currently separate the two— but there are some important common features. Normal anxiety is the response to threatening situ­ations. Feelings of apprehension are accompanied by physiological changes that prepare for defence or escape (‘fight or flight’), notably increases in heart rate, blood pressure, respiration, and muscle tension. Sympathetic nervous system activity is increased, causing symptoms such as tremor, sweating, polyuria, and diarrhoea. Attention and concentration are fo­cused on the threatening situation. Anxiety is a bene­ficial response in dangerous situations, and should occur in everyday situations of perceived threat (e.g. examinations). Abnormal anxiety is a response that is similar but out of proportion to the threat and/ or is more pro­longed, or occurs when there is no threat. With one exception, the symptoms of anxiety disorders are the same as those of a normal anxiety response. The ex­ception is that the focus of attention is not the external threat (as in the normal response) but the physio­logical response itself. Thus in abnormal anxiety, at­tention is focused on a symptom such as increased heart rate. This focus of attention is accompanied by concern about the cause of the symptom. Less

Problems due to use of alcohol and other psychoactive substances

Rebecca McKnight, Jonathan Price, and John Geddes

in Psychiatry

Archaeological evidence has demonstrated that for at least the past 10,000 years humans have been using psychoactive substances. From the chewing of coca ... More

Archaeological evidence has demonstrated that for at least the past 10,000 years humans have been using psychoactive substances. From the chewing of coca leaves in Ancient Peru (c.4000– 3000 bce) to the popular use of laudanum in Victorian England, the recreational, cultural, and medicinal use of ‘mind- altering’ substances has been widespread. As of 2016, alcohol and other psychoactive substances remain a leading cause of medical and social problems world­wide: humans are clearly vulnerable to their attrac­tion. Although a myriad of substances are available, only a few are commonly used, and all tend to produce similar harms upon the individual and society. This chapter will provide a general approach to managing a patient presenting with a problem stemming from substance misuse. It is extremely difficult to gather accurate data on the use of substances in the general population, especially if they are illegal. It is therefore likely that most figures are underestimations of the true incidence. The WHO estimates that tobacco, alcohol, and illicit drugs are a factor in 12.4 per cent of all deaths worldwide. This is a stark reminder of the severity that problems associated with substance usage can reach, but the morbidity sur­rounding them affects a much wider section of society. In the UK, 80 per cent of adults drink alcohol, 19 per cent smoke tobacco, and 30 per cent admit to having used an illegal drug at least once in their lifetime. Worldwide, the highest prevalence of drug misuse is found in the 16- to 30- year age group, with males outnumbering females at a ratio of 4 to 1. Table 29.1 shows a selection of epidemiological figures associ­ated with commonly used substances. Substance misuse is associated with an array of con­fusing terminology, the majority describing different disorders that may occur due to use of any substance. The following terms are internationally agreed and ap­pear in major classification systems:… ● Intoxication is the direct psychological and physical effects of the substance that are dose dependent and time limited. They are individual to the substance and typically include both pleasurable and unpleasant symptoms. Less

Drugs

Edward Shorter

in How Everyone Became Depressed: The Rise and Fall of the Nervous Breakdown

History has always known antidepressant remedies. In an era of faith, the faithful held to the Word as an augury of recovery: “cast down, but not destroyed.” But in a ... More

History has always known antidepressant remedies. In an era of faith, the faithful held to the Word as an augury of recovery: “cast down, but not destroyed.” But in a secular era and certainly by the middle of the twentieth century, pharmacological remedies were required. Indeed they were urgently indicated, for the diagnosis of depression itself was starting to spread. Because of Kraepelin and Freud, by 1940 depression had become a common term for serious psychiatric disease. An editorial in the Lancet called depression “perhaps the most unpleasant illness that can fall to the lot of man.” Depression was thus, while not terribly common, a considerable public health issue. What is puzzling in this story is that around 1940 depression began an inexorable, irreversible climb from awful but unusual to epidemic status. With the 1960s, depression started to become epidemic. One reason for the upswing in depression in mid-twentieth century was the cheering of the pharmaceutical industry. The drugs of the first generation of psychoactive medications were indicated for nervous disease, but there after the firms switched to depression because here were clearly the markets of the future. The early drugs represented an effective treatment for nervous disease. Their effect was sedation, and sedative drugs in medical practice go back to opium and to members of the belladonna family that have been known since Ancient times. Sedation means the process of calming, or allaying excitement. It does not necessarily involve the obtunding of consciousness, although large doses of sedatives may do that. Sedation means easing the pain of being, soothing the griefs and worries of existence, and calming the depressive and anxious agitation of the nervous syndrome. Although we all have worries and anxieties, we do not all have a pathological syndrome called nervousness. Historically, it was those with nerves who benefited from the early psychopharmacological treatments, beginning with the bromides at mid-nineteenth century. The first sedative made by chemical synthesis, chloral hydrate, was used clinically in 1869. A succession of sedatives from the organic chemical industry followed. Less

Context

Edward Shorter

in How Everyone Became Depressed: The Rise and Fall of the Nervous Breakdown

Consider the current landscape of depression. In an ABC poll in 2002, 15% of Americans said they felt “really depressed” once a week or more. Another 17% said once a ... More

Consider the current landscape of depression. In an ABC poll in 2002, 15% of Americans said they felt “really depressed” once a week or more. Another 17% said once a month. That means that one-third of the American population believes itself to be depressed in a given month. If you are riding on a subway train with a hundred other people, one-third of them will be currently depressed, or have just been, or are about to be. That is a lot. In fact, it is way too many. We know that only 3% of the population is chronically sad. We know that the serious disease, melancholia, is only a fraction of the ranks of the depressed. Far too many people have received the diagnosis of depression. Whose fault is this? At the beginning of our story, psychiatry spoke German. From around 1870 to 1933, German-speaking Europe was the epicenter of world psychiatry. This was so for two reasons. One, German, Swiss, and Austrian psychiatrists saw large numbers of very sick individuals because they practiced in mental hospitals, leaving outpatients to other practitioners. Of course this was true of alienists elsewhere, but there were more mental hospitals in Germany affiliated with universities because Germany had so many universities. Almost all had university psychiatric hospitals. This was not true elsewhere. So German psychiatry was oriented toward the academic study of large numbers of patients, and a genial figure such as Emil Kraepelin used these resources to make big strides. Second, German psychiatrists had a thorough familiarity with internal medicine because they were also trained as neurologists. From the viewpoint of subject matter, neurology has always been treated as a subspecialty of internal medicine, even though in Central Europe it was hived off to the nerve specialists. In learning so much neurology, German psychiatrists acquired a feeling for brain illness as involving the entire body: They were indeed attuned to looking at the body as a whole, in contrast to Anglo-Saxon psychiatrists, who usually did not also train as internists. Less

Generalized Anxiety Disorder

Vladan Starcevic, MD, PhD

in Title Pages

The main characteristics of generalized anxiety disorder (GAD) are chronic pathological worry, other manifestations of nonphobic anxiety, and various symptoms of ... More

The main characteristics of generalized anxiety disorder (GAD) are chronic pathological worry, other manifestations of nonphobic anxiety, and various symptoms of tension. Physical symptoms of anxiety are usually less prominent in GAD than in panic disorder, but they can still be an important component of clinical presentation. Behaviors that are often seen in other anxiety disorders, such as overt avoidance, are conspicuously absent. Unlike all other anxiety disorders, it is more likely for GAD in clinical setting to co-occur with a primary condition for which help has been sought–usually depression or other anxiety disorder–than to be the main reason for seeking professional help. Generalized anxiety disorder is one of the more controversial members of the family of anxiety disorders: it seems that almost every aspect of GAD has provoked debates that do not show signs of abating. Paradox, disagreement, debate, and controversy are the words most commonly associated with GAD. It is small wonder then that the list of ‘‘hot topics’’ related to GAD could be very long indeed. Listed below is a selection of issues thought to represent adequately a more comprehensive list…. 1. What are the characteristic features of GAD that would help in its conceptualization? Pathological worry, other cognitive aspects of anxiety, manifestations of tension, and/or (some) symptoms of autonomic arousal? What combination of these features would ensure that GAD is diagnosed adequately and recognized in clinical practice? 2. What is the relationship between pathological worry and GAD? 3. How can different views on what constitutes the essence of GAD be reconciled? Is GAD a single entity or are there two or more ‘‘types’’ of GAD with distinct clinical characteristics? 4. How is GAD related to depressive disorders, other anxiety disorders, and personality disturbance? Where are its boundaries? In view of its close relationship with depression, should GAD be classified along with depression and perhaps renamed accordingly? 5. Can GAD exist on its own, without depression or other anxiety disorders? What could be features specific enough for GAD that would allow it to establish itself as an independent and valid psychopathological and diagnostic entity? 6. What are the pathophysiological correlates of pathological worry and other aspects of chronic anxiety in GAD? 7. What are the underlying mechanisms and purpose of pathological worry in GAD? What is the meaning of chronic anxiety? Less