Neuronal plasticity

Neuronal plasticity
Neuronal plasticity is an essential component of neuronal adaptability and there is increasing evidence that this is primarily a biochemical rather than a morphological process. The neuron is not a fixed entity in terms of the quantity of transmitter it releases, and transmitters which are co-localized in a nerve terminal may be differentially secreted under different conditions. This, together with the repeated firing of some neurons that appear to have ‘‘leaky’’ membranes, may underlie the rhythmicity of neuronal activity within the brain. Plasticity is also evident at the level of the neurotransmitter receptors. These are fluid structures that can be internalized into the membrane so that their density, and affinity for a transmitter, on the outer surface of the nervemembrane may change according to functional need. Perhaps it is not surprising to find that our knowledge of how the brain works and where defects that lead to abnormal behaviour can arise is so deficient. The approach to understanding the biochemical basis of psychiatric disease is largely based on the assumption that the brain is chemically homogeneous, which is improbable! Nevertheless, there has been some success in recent years in probing the changes that may becausally related to schizophrenia, depression and anxiety. It should be apparent to anyone interested in the neurosciences that the brain is more than a sophisticated computer that follows a complicated programme, and any dogmatic approach to unravelling the complexities of this dynamic, plastic collection of organs which we call ‘‘brain’’ is doomed to failure.

Structure and function of nerve cells

Structure and function of nerve cells

Nerve cells have two distinct properties that distinguish them from all other types of cells in the body. First, they conduct bioelectrical signals for relatively long distances without any loss of signal strength. Second, theypossess specific intracellular connections with other cells and with tissues that they innervate such as muscles and glands. These connections determine the type of information a neuron can receive and also the nature of the responses it can .Essentially all nerve cells have one or more projections termed dendrites whose primary function is to receive information from other cells in their vicinity and pass this information on to the cell body. Following the analysis of this information by the nerve cell, bioelectrical changes occur in the nerve membrane that result in the information being passed to the nerve terminal situated at the end of the axon. The change in membrane permeability at the nerve terminal then triggers the release of the neurotransmitter. There is now evidence that the mammalian central nervous system contains several dozen neurotransmitters such as acetylcholine, noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), together with many more co-transmitters, which are mainly small peptides such as met-enkephalin and neuromodulators such as the prostaglandins. It is well established that any one nerve cell may be influenced by more than one of these transmitters at any time. If, for example, the inhibitory amino acids (GABA or glycine) activate a cell membrane then the activity of the membrane will be depressed, whereas if the excitatory amino acid glutamate activates the nerve membrane, activity will be increased. The final response of the nerve cell that receives all this information will thus depend on the balance between the various stimuli that impinge upon it. Although different neurotransmitters can be produced at different synapses within the brain, the individual neuron seems capable of releasing only one major neurotransmitter from its axonal terminal, for example noradrenaline or acetylcholine. This view was originally postulated by Sir Henry Dale in 1935 and was subsequently called Dale’s Law, not incidentally by Dale himself! It is now known that, in addition to such ‘‘classical transmitters’’, peptides and/or prostaglandins may also be co-released, and Dale’s Law has been modified in the light of such evidence. The nature of the physiological response to any transmitter will depend on the function of the target receptor upon which it acts. For example, acetylcholine released from a motor neuron will stimulate the nicotinic receptor on a muscle end-plate and cause muscle contraction. When the same neurotransmitter is releasedfrom the vagus nerve innervating the heart, however, it acts on muscarinic receptors and slows the heart. Recently it has become apparent that neurotransmitters can also be released from dendrites as well as axons. For example, in dendrites found on the cells of the substantia nigra dopamine may be released which then diffuses over considerable distances to act on receptors situated on the axons and dendrites of GABAergic and dopaminergic neurons in other regions of the basal ganglia. Another means of communication between nerve cells involves dendrodendritic contacts, where the dendrites from one cell communicate directly with those of an adjacent cell. In the olfactory bulb, for example, such synapses appear to utilize GABA as the main transmitter. Thus any neuron responding to inputs that may converge from several sources may inhibit, activate or otherwise modulate the cells to which it projects and, because many axons are branched, the target cells may be widely separated and varied in function. In this way, one neuron may project to an inhibitory or excitatory cell which may then excite, inhibit or otherwise modulate the activity of the original cell. As most neurons are interlinked in an intricate network the complexity of such transmitter interactions becomes phenomenal! In brief, neurons can be conceived as complex gates which integrate the data they receive and, via their specif c collection of transmitters and modulators, have a large repertoire of effects which they impose upon their target cells.

Some types of cells (In brain Function)

Some types of cells (In brain Function)
The neurons are surrounded by neuroglia (or glia) cells. These differ from the neurons in that they do not have electrically excitable membranes. They comprise nearly half the brain volume and function to separate and supportthe neurons. There are two main types of neuroglial cells, termed the macroglia and microglia. The macroglia are divided into the astrocytes, oligodendrocytes and ependymal cells. The astrocytes are characterized by long narrow cellular processes which give them a star-like structure; through their feet-like endings they can make contact with both the capillaries and neurons. It has been suggested that the astrocytes play a role in conducting nutrients from the blood to the neurons. Other roles include the removal by active transport of released neurotransmitters (particularly the inhibitory transmitter gamma-aminobutyric acid – GABA), the provision of precursors for transmitter synthesis (e.g. glutamine for the synthesis of GABA) and the buffering of the neuron against excessive concentrations of potassium ions formed following depolarization. Thus the astrocytes appear to play a critical role both in terms of physical protection of the neurons and in providing a metabolic buffer to ensure homeostasis. The oligodendrocytes occur in both grey and white matter. In white matter they form the insulating myelin sheath around the axon, whereas in grey matter they probably provide myelin for axons coursing through the grey matter. In the pe ipheral nervous system, these functions are fulfilled by the Schwann cells. The myelin is formed by the outgrowth of the plasma membrane of the oligodendrocyte which is wrapped several times around the axon, thereby excluding extracellular fluid from between the layers of the plasma membrane and thereby generating a highly insulating coat. This insulating coat, which is interrupted at the nodes of Ranvier, is important for the efficient transmission of the electrical impulses down the axon. The ependymal cells line the inner surfaces of the ventricles and, together with the neuroglial cells, appear to be involved in the exchange of material with the surrounding cerebrospinal fluid. The microglia can be considered as the macrophage cells of the brain whose function is to remove cell debris by a process of phagocytosis following neuronal damage. There is also evidence that the macroglia are involved in localized inflammatory processes within the brain and may play an important role in the cause of neurodegenerative diseases such as Alzheimer’s disease.Damage to brain tissue is associated with the proliferation of neuroglia. This s termed gliosis and is associated with an increase in the number of macroglia and microglia. Scar tissue is frequently associated with gliosis.

The role of the blood–brain barrier

The role of the blood–brain barrier

Although the brain constitutes only 2% of body weight, it receives approximately 15% of the blood supply and consumes nearly 20% of the total oxygen and glucose available to the body. In order to supply these essential nutrients for brain function, there must be a consistent and rapid blood supply to the brain in order that the brain cells may function. This is supplied by the cerebral arteries derived from the internal carotid arteries which branch over the surface of the brain and send smaller branches into the deeper subcortical structures. The capillaries are highly branched and it has been calculated that every nerve cell is no more than 40–50 mm from a capillary. Because of the unique dependence of the brain on oxygen and glucose to enable the extensive oxidative metabolism to take place within the nerve cells, it is essential that the composition of nutrients, electrolytes, etc. in the fluid surrounding the brain cells is controlled. The composition of the blood varies to some extent according to the composition of the diet and therefore a mechanism has evolved to ensure that the composition of the extracellular fluid surrounding the brain cells is constant. The extracellular fluid is inequilibrium with the cerebrospinal fluid which fills the four ventricles of the brain, and covers the surface of the brain and the spinal cord. Cerebrospinal fluid is formed from the blood and may be considered as an ultra filtrate of plasma. Thus cerebrospinal fluid contains most of the electrolytes and low molecular weight nutrients but is low in protein. It is formed from a network of capillaries in the ventricles termed the choroids plexus but the cerebral capillaries also contribute to the production of cerebrospinal fluid. The extracellular fluid and the cerebrospinal fluid compartment is separated from the blood by the blood–brain barrier. This is a barrier formed by tight junctions that exist between the endothelial cells lining the capillaries and the epithelial cells at the choroid plexus. Such a barrier prevents the influx of large molecular weight molecules but enables small molecular weight substances such as glucose, amino acids, fatty acids, electrolytes, etc., which are essential for normal brain function, to enter. In addition to the structural nature of the blood–brain barrier, there also exist specific transport sites that assist the transport of glucose and essential amino acids into the extracellular fluid. Thus the blood–brain barrier has both a structural and a metabolic role to play in maintaining homeostasis. Cellular structure of the brain It has been calculated that the human brain contains approximately 10712 neurons of which the cortex probably contains 10710. Such complexity is further magnified by the neuronal interconnections. Structurally the neuronal cell body contains a number of organelles that are characteristic of all cell types. The most important features are the nucleus, which contains the deoxyribonucleic acid (DNA) together with specific proteins that form chromosomes, and which functions to control the synthesis of all molecules within the neuron, and the nucleolus which is involved in ribosome synthesis and in the transfer of ribonucleic acid (RNA) to the cytosol. There is now evidence that the messenger RNA forming specific proteins is targeted to specific parts of the nerve cell. For example, the messenger RNA for microtubule associated protein-2 (MAP-2) targets the dendrites. This provides a mechanism for maintaining the structural integrity and differentiation of the neuron. The mitochondria, as in all types of cells, provides energy to the nerve cell in the form of adenosine triphosphate (ATP). The smooth endoplasmic reticulum is involved in lipid synthesis and in protein glycosylation whereas the rough endoplasmic reticulum is formed from the attachment of ribosomes to the smooth endoplasmic reticulum. These ribosomes are the main sites of membrane protein synthesis.The Golgi apparatus is situated near the nucleus and is responsible for protein glycosylation, membrane assembly and protein sorting. Lysosomes are responsible for the degradation of all types of cellular debris. The plasma membrane surrounds the neuron and consists of a phospholipid bilayer, inserted into which are intrinsic and extrinsic membrane proteins and cholesterol. The plasma membrane provides an impermeable barrier for many large molecular weight and charged molecules. The plasma membrane is transversed by different types of proteins that act as
neurotransmitter receptors and voltage-sensitive ion channels.The cytosol is the fluid compartment of the cell and contains the enzymes responsible for cellular metabolism together with free ribosomes concerned with local protein synthesis. In addition to these structures which are common to all cell types, the neuron also contains specific organelles which are unique to the nervous system. For example, the neuronal skeleton is responsible for monitoring the shape of the neuron. This is composed ofseveral fibrous proteins that strengthen the axonal process and provide a structure for the location of specific membrane proteins. The axonal cytoskeleton has been divided into the internal cytoskeleton, which consists of microtubules linked to filaments along the length of the axon, which provides a track for the movement of vesicular material by fast axonal transport, and the cortical cytoskeleton. The cytoskeleton is found near the axonal membrane and consists of microfilaments linked internally to microtubules and the plasma membrane by a network of filamentous protein that includes the brain-specific protein fodrin. This protein forms attachment sites for integral membrane proteins either by means of the neuronal cell adhesion molecule (N-CAM) or indirectly by means of a specific protein called ankyrin in the case of the sodium channels. This may provide a means whereby the sodium channels are concentrated in the region of the nodes of Ranvier. Thus the cortical cytoskeleton plays a vital role in neuronal function by acting as attachment site for various receptors and ion channels, but also for synaptic vesicles at nerve terminals, thereby providing a mechanism for concentrating the vesicles prior to the release of the neurotransmitter. There is also interest in the involvement of the cytoskeleton in such dgenerative diseases as Alzheimer’s disease whichis characterized by tangles (paired helical filaments). It seems likely that one of the microtubule-associated proteins (tau protein) is an important component of the tangles found in Alzheimer’s disease. Another unique feature of the neuron is the presence of synaptic and coated vesicles. The former are small smooth-coated vesicles 30–100nm in diameter and containing the neurotransmitters. The latter are rough-coated vesicles that contain the protein clathrin. These are thought to be involved in the retrieval and recycling of membrane components including the synaptic vesicles once they have liberated their neurotransmitter into the synaptic cleft.

Neuroanatomy of the Brain

Neuroanatomy of the Brain
The brain described in terms of its general structure and key anatomical areas. It may also be described in terms of the cellular or subcellular structure of the different types of cells that constitute the brain. Finally it is considered in terms of its functional importance in memory, consciousness and control of bodily functions. However the brain is described, each level of organization is essentially linked to another level of organization. Conventionally, neuroscientists have concentrated on the structural aspects of the brain and its cellular components while psychologists and psychiatrists have concentrated on the more functional aspects such as consciousness, thought processing and emotion. With the advent of sophisticated imaging methods and the introduction of novel drugs that combine therapeutic efficacy with subcellular specificity of action, it is now possible to show how all the levels of brain structure and function are interlinked.The principal regions of the human brain which are important in psychiatry and neurology .

Structural and functional subdivision of the brain

In brief, the brain may be divided into the brainstem (consisting of the medulla, pons and midbrain) that is linked to the diencephalon which is composed of the thalamus and the hypothalamus. The two cerebral hemispheres are linked by the corpus callosum, (a large tract of nerve fibres that enables the two)
Amygdala – An anatomically coherent subsystem within the basal forebrain. Verbal and non-verbal expressions of fear and anger are interpreted by the amygdala.
Cerebellum – One of the seven parts of the brain that is responsible for muscle co-ordination and modulation of the force and range of movement. It is involved in the learning of motor skills.
Cortex – The most highly developed area in humans and divided into four main regions, namely frontal, parietal, temporal and occipital. The cortex mediates and integrates higher motor, sensory and association functions.
Dorsal raphe´ – Main serotonin (5-HT)-containing neurons that project through the brain.Other raphe´ neurons project down the spinal cord where they act as a gating mechanism for pain perception from the periphery. Main activity is in the regulation of mood, anxiety, sexual behaviour, sleep.
Hippocampus – Region primarily concerned with learning and short-term memory.
Hypothalamus – Part of the diencephalon comprising several nuclei where hormones such as oxytocin and antidiuretic hormone are synthesized and pass to the pituitary gland. Involved in the regulation of the peripheral autonomic system and pituitary hormones such as prolactin, growth hormone and adrenocorticotrophic hormone.
Locus coeruleus – Collection of cell bodies containing about 50% of the noradrenergic neurons. Main activity is in the regulation of mood, anxiety and attention. Noradrenergic tracts innervate most regions of the brain.
Thalamus – This acts as a relay station for pain, temperature and other bodily sensations.halves of the brain to communicate. The brain is permeated by four ventricles, the two largest of which occur beneath the cerebral cortex.

The basal ganglia consists of the corpus striatum (consisting of the caudate nucleus, globus pallidus and putamen) and the substantia nigra. This region is concerned primarily with the control of movement and is malfunctional in Parkinson’s disease and Huntington’s disease. It is apparent that the brain is really an assembly of organs all of which are structurally and functionally interconnected. Undoubtedly one of the most important areas for the psychopharmacologist is the so-called limbic system which is concerned with emotion. This region consists of the hippocampus (concerned with memoryprocessing), the thalamus and hypothalamus (concerned with the control of the endocrine system, temperature regulation, feeding, etc.), the amygdale and septum (the emotional centres of the subcortex), the fornix and the cingulate gyrus of the cortex. The cerebral cortex is conventionally subdivided into four main regions that may be delineated by the sulci, or large clefts, termed the frontal, temporal, parietal and occipital lobes. These names are derived from the bones of the skull which overlay them. Each lobe may be further subdivided according to its cellular structure and composition. Thus Brodmann has divided the cortex into approximately 50 discrete areas according to the specific cellular structure and function. For example, electrical stimulation of the strip of cerebral cortex in front of the central sulcus is responsible for motor commands to the muscles. This is termed the primary motor cortex and can be further subdivided according to which muscles are controlled in different parts of the body. Similar maps exist in other parts of the brain; for example, the areas concerned with sensory input such as the primary somatosensory cortex . Such brain maps of the body are important because information from various organs converge on the brain in a highly organized fashion and can therefore be reflected at all levels of information processing. Suchintegration also allows the brain to obtain a true representation of the external environment as projected by the sensory organs. The functional importance of specific cortical and subcortical regions of the brain may also be elucidated by studying the consequences of specific neurological lesions. For example, it has been shown by imaging methods that blood flow to the hippocampus of patients with Alzheimer’s disease is dramatically reduced, the reduction paralleling the degree of short-term memory impairment. In addition, blood flow to the parietotemporal association cortex is also greatly reduced. Such changes in he functional activity of these brain areas may account for the memory and cognitive deficits that are symptomatic of the disease, the main function of the parietotemporal association cortex being the integration of sensory and cognitive processes in the brain.

DSM-III AND DSM-III-R

DSM-III AND DSM-III-R
Spitzer and his colleagues developed computer programs called DIAGNO and DIAGNO-II that were designed to use the syndromalinformation gathered by the Mental Status Schedule to assign more reliable clinical diagnoses.To develop an empirically based, more reliable diagnostic system, researchers at Washington University published an importa,nt article in 1972 that set forth explicit diagnostic criteria—the so-called Feighner criteria—for 16major disorders. Their intent was to replace the vague and unreliable descriptions of DSM-I and DSM-II with systematically organized,.This help researchers to establish the diagnostically homogeneous and predictively valid experimental groups for which they had long striven in vain. The format of the Feighner criteria greatly influenced the format for diagnostic criteria adopted in DSM-III. A derivative of Feighner’s work, the Research Diagnostic Criteria (RDC), developed jointly by the New York State Psychiatric Institute and Washington University groups . Designed to permit empirical testing of the presumably greater reliability and validity of the Feighner criteria, the RDC criteria yielded substantially greater diagnostic reliability than the equivalent DSM-II disorders and so constituted a great step forward Drawing largely from the groups that formulated the RDC—psychiatry faculty at the Washington University School of Medicine in Saint Louis and the Columbia University College of Physicians and Surgeons in New York—neo-Kraepelinian diagnostic research during the 1970s laid the groundwork for the revolutionary advances of DSM-III. Like Kraepelin himself, the neo-Kraepelinians endorsed the existence of a boundary between “pathological functioning” and “problems in living,” viewed mental illness as the purview of medicine, and believed in the importance of applying the scientific method so
that the etiology, course, prognosis, morbidity, associated features, family dynamics, predisposing features, and treatment of psychiatric illnesses could be elucidated more clearly.
Five years after the RDC criteria were published, DSM-III appeared (APA, 1980), heralding substantial advances in the reliability, validity, and utility of syndromal diagnosis. Based in large part on the RDC, the inclusion in DSM-III of rigorously designed diagnostic criteria and, in an appendix, diagnostic decision trees, represented the new instrument’s most significant advance. The criteria were designed to organize each syndrome’s distinguishing signs and symptoms within a consistent format—they were, in scientific parlance, operationalized, so that each clinician who used them would define each sign and symptom the same way, and process the resulting diagnostic information in a consistent manner. This degree of detail in the diagnostic information available to DSM-III’s users contrasted sharply with the paucity of such detail in DSM-I and DSM-II.
Several structured and semistructured diagnostic interviews based on the DSM-III, very distant descendants of the Mental Status Schedule and the Psychiatric Status Schedule, were published around the time DSM-III appeared, in a related effort to enhance diagnostic reliability and, especially, to spur research. The best known of these was the NIMH Diagnostic Interview Schedule (DIS; Robins, Helzer, Croughan, & Ratcliff, 1981), a structured interview designed for nonclinician interviewers. The semistructured Structured Clinical Interview for DSM-III (SCID; Spitzer, 1983; Spitzer & Williams, 1986), designed for use by clinicians, was also published around the same time. These important, and in most ways unprecedented, new instruments provided the data-gathering structure both for major new epidemiologic efforts (e.g., Epidemiologic Catchment Area study [Regier et al., 1984], National Comorbidity Survey [e.g., Kessler, Sonnega, Bromet, Hughes, & Nelson, 1995; Kessler, Stein, & Berglund, 1998]) and for a host of clinical and preclinical studies, because they insured the internal validity of the research by helping ensure that the samples of human psychopathology were well characterized diagnostically. DSM-III-R, published in 1987, was a selective revision of DSM-III that retained the advances of the 1980 instrument and incorporated generally modest changes in diagnostic criteria that new clinical research (to a great extent dependent on findings produced by the application of the DIS and SCID to human research samples) suggested should be a part of the diagnostic system. It was in this way that diagnostic research “bootstrapped” its way from the dismal days of Rosenhan to the well-regarded science it is today, and its products, although not universally successful, have been impressive indeed.DSM-III and DSM-III-R addressed their predecessors’ disappointing diagnostic validity and utility in several ways (Spitzer et al., 1980). To begin with, both volumes are much larger than their predecessors, in part to accommodate inclusion of more than three times as many diagnoses, in part to provide detailed information on each syndrome along with its defining diagnostic criteria. The expansion of syndrome descriptions made it easier for clinicians to describe more precisely their patients’ behavior, and to understand their suffering in the context of their milieu.
Another advantage of DSM-III and DSM-III-R was that they assessed patients along five imensions, or axes: Psychopathology was diagnosed on Axes I and II; medical conditions
impacting on the mental disorders were noted on Axis III; the severity of psychosocial stressors affecting the patient’s behavior was noted on Axis IV; and the patient’s highest level of adaptive functioning was noted on Axis V. The additional information available from multiaxial diagnosis was presumed to be more useful for treatment planning and disposition than the single diagnostic label available from DSM-I and DSM-II.

A very substantial number of reliability studies of the DSMIII and DSM-III-R diagnostic criteria were published. Almost without exception, they pointed to much greater diagnostic stability and interrater agreement for these instruments than for their predecessors, DSM-I and DSM-II. Enhanced reliability was especially notable for the diagnostic categories of schizophrenia, bipolar disorder, major depressive disorder, and substance abuse and dependence; the reliability of the personality disorders, some of the disorders of childhood and adolescence, and some of the anxiety disorders has been less encouraging (e.g., Fennig et al., 1994; Klein, Ouimette, Kelly, Ferro, & Riso, 1994; Mattanah, Becker, Levy, Edell, & McGlashan, 1995), but this has been due to a variety of
reasons, including conceptual underspecification (in the case of the personality disorders), and the inherently transitory of self-correcting nature (diagnostic stability problems) of some others (disorders of childhood and adolescence and some forms of anxiety).
Thus, despite these explicit efforts to enhance the diagnostic utility and validity of DSM-III and DSM-III-R, it did not prove easy to document the impact of these efforts. The absence of documented etiological mechanisms, with associated laboratory findings, by which the diagnoses of many physical disorders are confirmed—the “gold standard”—made establishing the construct validity of many DSM-III and DSM-III-R diagnoses difficult (Faraone & Tsuang, 1994). As noted later in this chapter, the same problem continues to stand in the way of attempts to validate DSM-IV diagnoses.
Although the DSM-III and DSM-III-R diagnostic criteria enhanced the instruments’ diagnostic reliability, diagnostic stability continued to be an issue for diagnosticians because of changes in patient functioning over time. Thus, in a study of the six-month stability of DSM-III-R diagnoses in firstadmission patients with psychosis, Fennig et al. (1994) reported that whereas affective psychosis and schizophrenic disorders showed substantial diagnostic stability, stability for subtypes of these conditions was less stable. Changes in patient functioning were seen as responsible for 43 percent of these diagnostic changes. In like fashion, Nelson and Rice (1997) reported that the one-year stability of DSM-III lifetime diagnoses of obsessive-compulsive disorder (OCD) turned out to be surprisingly poor: Of OCD subjects in the ECA sample they followed, only 19 percent reported symptoms a year later that met the OCD criteria. Mattanah and his colleagues (1995) reported that the diagnostic stability of several DSM-III-R disorders was lower for a group of adolescents two years after hospitalization than for the same diagnoses given adults. These and similar studies of diagnostic stability emphasized the extent to which diagnostic reliability is dependent not only on the validity of diagnostic criteria but on the inherent symptom variability of disorders over time as well.
Also, researchers using DSM-III and DSM-III-R diagnostic criteria undertook research during the years following their appearance to validate several of the manual’s major diagnostic categories, including schizophrenia and major depressive disorder, despite the absence of a gold-standard criterion of validity. Our brief mention of validation studies includes only Kendler’s familial aggregation and coaggregation research findings, both because they represent a particularly powerful approach to validation and because the findings generally mirror those found by others, but many others could be adduced.
When Kendler, Neale, and Walsh (1995) examined the familial aggregation and coaggregation of five hierarchically defined disorders—schizophrenia, schizoaffective disorder, schizotypal/paranoid personality disorder, other nonaffective psychoses, and psychotic affective illness—in siblings, parents, and relatives of index and comparison probands, they reported that although schizophrenia and psychotic affective illness could be clearly assigned to the two extremes of the schizophrenia spectrum, the proper placement of schizoaffective disorder, schizotypal/paranoid personality disorder, and other nonaffective psychoses could not be clearly made. In a companion report, Kendler and his coworkers (1995) found that probands with schizoaffective disorder differed significantly from those with schizophrenia or affective illness in lifetime psychotic symptoms as well as outcome and negative symptoms assessed at follow-up. Moreover, relatives of probands with schizoaffective disorder had significantly higher rates of schizophrenia than relatives of probands with affective illness.
Although Kendler’s family research method validated only a portion of schizophrenic spectrum disorder diagnoses, he and his colleagues (Kendler et al., 1996; Kendler & Roy,
1995) were able by the same methods to strongly support the validity of the DSM-III major depression diagnostic syndrome. However, when Haslam and Beck (1994) tested the content and latent structure of five proposed subtypes of major depression, clear evidence for discreteness was found only for the endogenous subtype; the other proposed forms lacked internal cohesion or were more consistent with a continuous or dimensional account of major depression.

Criticisms
Although DSM-III and DSM-III-R represented major advances, they were widely criticized. This was particularly so for DSM-III, the first manual to truly shatter the mold in which prior nosologies had been cast. One major source of concern was that DSM-III incorporated more than three times the number of diagnostic labels in DSM I. Prominent clinical child psychologist Norman Garmezy expressed the concern that this proliferation of diagnostic labels would tempt clinicians to pathologize unusual but normal behaviors of childhood and adolescence, a criticism more recently directed at DSM-IV (Houts, 2002). In a similar vein, social workers Kirk and Kutchins (1992) accused the instrument’s developers of inappropriately labeling “insomnia, worrying, restlessness, getting drunk, seeking approval, reacting to criticism, feeling sad, and bearing grudges . . . [as] possible signs of a psychiatric illness” (p. 12). Thus, the definition of mental disorder developed for DSM-III (and retained in DSM-III-R and DSM-IV) has been criticized for being both too broad and encompassing of behaviors not necessarily pathological, and for offering poor guidance to clinicians who must distinguish between uncommon or unusual behavior and psychopathological behavior.
Addressing these concerns, Spitzer and Williams defended the DSM-III approach (and by extension, the entire ensuing DSM tradition) by noting that the intention of the framers was to construct a nomenclature that would cast as wide a clinical net as possible, in order that persons suffering from even moderately disabling or distressing conditions would receive the help they needed. But overdiagnosis was not the only rifle leveled at the DSM tradition. Schacht and Nathan ,Schacht , and others questioned the frequent emphasis in DSM-III on disordered brain mechanisms in its discussions of etiology, as well as its apparent endorsement of pharmacological treatments in preference to psychosocial treatments for many disorders. In response, Spitzer noted that the DSM-III text simply reflected the state of knowledge of etiology and treatment. Similar concerns have been voiced about DSM-IV by Nathan and Langenbucher .
DSM-III and its successors have also been criticized for their intentionally atheoretical, descriptive position on etiology. In a debate on these and related issues these critics charged that an atheoretical stance ignored the contributions of psychodynamic theory to a fuller understanding of the pathogenesis of mental disorders, as well as to the relationship between emotional conflict and the ego’s mechanisms of defense. But in the same debate, Spitzer questioned the empirical basis for the claim that psychodynamic theory had established the pathogenesis of many of the mental disorders.