From Pathophysiology To Pathogenesis

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A clear description of pathophysiological processes is essential for the generation of insights into underlying pathogenic processes. At one time, there was the hope that psychiatric disorders would turn out to be as simple as gout, where elevated uric acid levels lead to buildup at susceptible joints causing inflamed tissues and excruciating pain. Elimination of uric acid buildup (whether by blockade of synthesis with allopuri-nol or reduced ingestion of purine precursors) eliminates the proximal causes and all the symptoms of gout. In a sense, the classic biogenic amine theories of psychopathologies were based on the expectation that such exquisitely linear logic might apply to certain mental disorders (e.g., Schildkraut, 1965). Unfortunately, they have not. Indeed, there has been movement to conceptualize psychiatric disorder more in terms of nonlinear dynamic perturbations (Tschacher et al., 1997), perhaps with basic emotional systems being strange attractors within such hypercomplex systems.

Without adequate pathophysiological foundations, the clarification of pathogenesis is bound to be limited. The tripartite cascade of analysis applies here as with any scientific question: First, one has to identify the correlates of the phenomena in which one is interested. Second, one has to determine whether or not the correlates actually have any relevant causal influences in the system. Finally, one has to develop a "mechanistic" theory of how the system operates. This has not been achieved for any of the classic psychiatric disorders, but the goal is being approximated for certain new degenerative disorders with psychotic implications (e.g., Chapters 14 and 15).

Alzheimer's disease and other dementias are classic neuropsychiatric examples of how a careful analysis of pathophysiology has gradually led the way to a deep molecular understanding of pathogenesis. From the initial description of the pathology of restricted cortical areas, the gradual revelation of underlying genetic factors that predispose one toward such degenerative processes has finally emerged (Chapter 15). This knowledge is now slowly being translated into new and more effective therapies.

Typically, schizophrenia has been the "gold standard" by which our understanding of psychiatric disorders will be judged. During much of the 20th century there were abundant reports of both neuroanatomical and biochemical correlates, but the patterns did not begin to gel until the past few decades. The most striking discovery was the enlargement of the ventricles, which suggests a neurodevelopmental disorder that may have multiple causes (see Chapter 9). The fact that among identical twins only the afflicted siblings exhibited the brain deficit suggests the contribution of nongenetic factors. The misarrangement of nerve cells also suggests that this type of brain impairment could have both genetic and gestational (perhaps viral) underpinnings. If misconnections in the brain are the critical causal feature, as opposed to dynamic neurochemical imbalances, then even the best medicines are bound to be simply beneficial for symptomatic control of the disorder with no realistic hope for a cure, as seems to be the case in pervasive developmental disorders (Chapter 14). For instance, the selective death of GABAergic cells in frontal areas may set in motion the disregulation of dopamine systems, which can be partly alleviated by antipsychotics. However, early interventions might still offer hope for better long-term management of the disease processes.

Most psychiatric disorders exhibit substantial genetic loadings, and for some childhood syndromes, such as Williams and Rett's syndromes, the details have been worked out (Chapter 14). Studies in molecular pathogenesis continue to promise remarkable riches in understanding many neuropsychiatric problems. The pervasive consequences of trinucleotide repeats in certain genes are now widely recognized. The most prominent ones for psychiatry are Huntington's disease and fragile X syndrome, in which a good protein is converted to a dysfunctional one by the addition of "junk" deoxyri-bonucleic acid (DNA) to a coding site. The resulting synthesis of poorly constructed proteins has cascading consequences in brain function. The fact that certain genetic influences such as trinucleotide repeats can expand generation by generation is now seen as a potential factor for the increasing incidence and severity of certain disorders (e.g., Huntington's disease). The identification of such disease vectors permits us to offer a definite diagnosis, usually leading to the designation of a distinct syndrome. For instance, the autistic-like mental impairment of fragile X children is now recognized as a separate medical entity (Chapter 14).

With the discovery of pathophysiological correlates that characterize specific disorders, the clarification of pathogenic causes is greatly facilitated. During the 20th century, some advances were made. Perhaps the most striking was the recognition of the devastating influences of early social loss (Bowlby, 1969) and other debilitating effects of stress (Chapter 4) that have many parallels in animal models (for a review, see Panksepp, 2001). Although the discovery of this relationship in humans came first, the cause will only be worked out by studies of other species. It is now generally recognized that the stress of social loss (whether it be in the form of separation distress or defeat in social encounters) may be a major factor in the precipitation of depressive disorders (Heim and Nemeroff, 1999). The emerging genetic data will be especially valuable in helping characterize the Axis II personality vulnerabilities that may increase susceptibility to certain emotional imbalances (Chapter 5).

The discovery of environmental vectors can rapidly lead to prophylactic maneuvers. The classic examples are the alleviation of mental retardation induced by phenylketonuria by the elimination of the toxic agent, phenylalanine, from the diet. Such a strategy, unfortunately, can currently be implemented in only a few metabolically induced disorders. For most organic disorders, the development of new therapies will require effective simulation of the disease processes in laboratory animals. To be effective, the animal models will have to be sufficiently homologous to critical aspects of a disease process so that effective translations can be made to the human condition. In the area of emotions, this remains a contentious issue that will only be resolved by the eventual achievement of practical success (Chapters 16 and 21).

Table 1.1 summarizes a highly simplified model of what a future brain-systems-based diagnostic scheme may look like. One reading of modern neuroscience (i.e., Panksepp, 1998) is that there is a limited but widely ramifying set of core emotional systems that regulate various instinctual urges critical for survival. These include systems that control appetitive-exploratory tendencies, anger-irritability, fear-anxiety, male and female eroticism, maternal nurturance, social bonding and separation distress, playful interactions, and a variety of bodily needs (thirst, hunger, and sleep). Another axis in this type of scheme would have to be based on an understanding of the status of the more general state-control systems (Fig. 1.1). Depression, for example, may reflect a global depletion of many of these neuroemotional resources (highlighted in Table 1.1 and Fig. 1.1), especially in those systems that facilitate positive emotions most prominently.

Of course, each core emotional system has complex neural substrates, with multiple interrelations among the various emotions, as well as diverse cortico-cognitive thinking structures they energize. Thus, even with such a "natural kind" of classificatory scheme, there is bound to be movement from the categorical description of major emotional disorders to the level of subspecies and mixed species. That seems inevitable as we focus on newly discovered details of the underlying processes. Still, the great challenge for the 21st century will be to coherently link the major psychiatric diseases to the basic evolved functions of the brain—to the activities of emotional systems, consciousness processes, as well as cognition and memory substrates (Chapters 2 and 3).

Such alternative conceptual schemes for the underpinnings of major psychiatric problems (Table 1.1) could also guide new drug developments and therapeutic programs in productive ways. Each emotional system is characterized by its own, at times unique, neuropeptidergic neuromodulators (Panksepp, 1998), which may become targets for novel therapeutic strategies (see Chapter 21). Viewing psychiatric disorder in this way, with reference to major emotional systems of the brain and their many general

TAB LE 1.1. Postulated Relationships Between Basic Emotional Systems, Common Emotional Processes, and Major Psychiatric Disorders3 0

Basic Emotional

Related

Systemc

Emergent Emotions

Emotional Disorders

SEEKING (+ and -)

Interest

Obsessive-compulsive

Frustration

Paranoid schizophrenia

Craving

Addictive personalities

RAGE (- and +)

Anger

Aggression

Irritability

Psychopathic tendencies

Contempt

Personality disorders

Hatred

FEAR (-)

Simple anxiety

Generalized anxiety disorders

Worry

Phobias

Psychic trauma

Post traumatic stress disorder variants

PANIC (-)

Separation distress

Panic attacks

Sadness

Pathological grief

Guilt/shame

Depression

Shyness

Agoraphobia

Embarrassment

Social phobias, autism

PLAY (+)

Joy and glee

Mania

Happy playfulness

ADHD

LUST (+ and -)

Erotic feelings

Fetishes

Jealousy

Sexual addictions

CARE (+)

Nurturance

Dependency disorders

Love

Autistic aloofness

Attraction

Attachment disorders

aThe last two columns provide hypotheses of the major relationships. Obviously, multiple emotional influences contribute to each of the emergent emotions (e.g., jealousy is also tinged by separation distress and anger), and all the emotional disorders have multiple determinants. Plus and minus signs after each indicate major types of affective valence that each system can presumably generate (adapted from Panksepp, 2000) b Capitalizations are used to designate the various emotional systems to highlight the fact that these are instantiated as distinct neural entities rather than simply psychological concepts. The essential neural components constitute command influences that coordinate the basic behavioral, physiological, and psychological aspects of each emotional response. cFrom Panksepp (1998, 2000).

aThe last two columns provide hypotheses of the major relationships. Obviously, multiple emotional influences contribute to each of the emergent emotions (e.g., jealousy is also tinged by separation distress and anger), and all the emotional disorders have multiple determinants. Plus and minus signs after each indicate major types of affective valence that each system can presumably generate (adapted from Panksepp, 2000) b Capitalizations are used to designate the various emotional systems to highlight the fact that these are instantiated as distinct neural entities rather than simply psychological concepts. The essential neural components constitute command influences that coordinate the basic behavioral, physiological, and psychological aspects of each emotional response. cFrom Panksepp (1998, 2000).

modulators such as the biogenic amines, may eventually help open a route past some of the conundrums of DSM-IV (McHugh, 2001).

An understanding of the basic emotional systems we share with other mammals is already shedding important new light on acquired behavior disorders such as substance abuse. Such tendencies are based upon natural psychobehavioral urges (mediated partly by mesolimbic dopamine systems) that motivate organisms to pursue resources needed for survival. This generalized appetitive SEEKING system of the brain energizes the instinctual apparatus for goal-directed behavior, but it can be commandeered and short-circuited "to run after its own tail," so to speak, as occurs when addictive drugs directly arouse this hedonically positive life-sustaining system. All the abused drugs from alcohol to nicotine release dopamine to some extent, leading organisms to perpetuate associated activities. As the arousal of this instinctual system becomes linked with the contingencies of drug acquisition and administration, free choice becomes constrained by the newly acquired conditional "drives." Thus this basic brain system that regulates the urge to pursue resources needed for survival becomes entrapped in a maladaptive vicious cycle. Similar processes may be operating in sexual addiction and various appetite control disorders.

This example highlights how the functional nature of certain brain systems can guide theorizing about underlying processes. However, our recognition of such systems is only the first step in the harvesting of psychiatrically useful knowledge. The actual details of how these systems operate will presumably provide insights on how they can be selectively modulated. Unfortunately, the recognition of such psychobio-logical constructs has been slow during this most recent molecular era of psychiatry because a widespread assumption has prevailed—one similar to that which characterized behavioristic psychology: that we could forego a deep psychological analysis of brain functions and move directly from DSM symptom-based diagnostics to underlying molecular causes. It now seems increasingly clear that this may not be possible. We do need psychological and psychoanalytic concepts to wrap our minds around what is happening to people in emotional distress. And it is not just cognitive concepts that are needed but sufficiently well-resolved affective ones as well (Ostow, 2003).

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