Leon Cytryn, MD

The past decade witnessed major strides in our understanding and treatment of affective disorders in adults, children and adolescents. One of the baffling problems in child and adolescent psychiatry was the question of psychiatric illness spanning a lifetime. The existence of depressive disorders in prepubertal children has been generally recognized and acknowledged since the 1960s; however, only in the last decade did evidence become available that supports the notion that depression in different ages represents the same entity, albeit manifesting different clinical symptoms in each developmental period (Cytryn and others 1986).

A clinical similarity is already evident in 5- to 6-year-old children, which permits to diagnosing mood disorders at this age using modified adult rating scales and unmodified adult diagnostic criteria. A developmental continuity is also suggested by the fact that many biological markers found in major depressive disorders approximate adult values with advancing age. These include: EEG sleep patterns, hypersecretion of cortisol, diminished growth hormone to an insulin tolerance test and diminished 24-hour 3-methoxy-4-hydroxy phenylglycol (MHPG) excretion in the urine (Cytryn, McKnew 1980). 

In addition, several follow-up studies indicate that (1) prepubertal mood disorders often continue into adolescence and adulthood (Asarnow and colleagues; Kovacs and others); (2) many children who develop depressive disorders in childhood will have at least one relapse before the age of 15 (Weissman and others); (3) dysthymic disorder, the most common form of mood disorder in prepubertal children, frequently converts to major depressive disorder in adolescence and usually has a protracted, chronic course (Kovacs and coworkers). In fact, it has been suggested that early onset of a depressive disorder may foretell a more severe course of the illness, similar to that found in juvenile forms of rheumatoid arthritis and diabetes; and (4) bipolar disorder is being diagnosed in children with increasing frequency, and of those with a severe unipolar disorder before puberty, at least 20% become bipolar during late adolescence. 

The modern understanding of genetic factors started with the discovery of the deceptive simplicity of our genetic code, based on a variable arrangement of only four organic bases-adenine, guanine, thymine and cytosine. This discovery opened the way for the remarkably rapid progress in genetic research, aided by impressive advances in molecular genetics in the last two decades. In rapid succession, the discovery of restriction enzymes, followed by such ingenious breakthroughs as the polymerase chain reaction and genetic sequencing, generated a dizzying speed in the process of gene mapping, i.e., identification and correct localization of up to 100,000 human genes. 

This gigantic effort has been appropriately recognized and nurtured by the Human Genome Project, started in the 1980s by the National Institute of Health. It was originally estimated that the process of mapping the entire human genome may not be completed until several decades into the 21st century. However, as the rapid pace of genetic discoveries continues, abetted by the involvement of the private sector, the completion of the task looms much closer on the horizon. Some estimates are a mere several years after the turn of the century, providing a fitting entry into the third millennium. 

 In the 1980s, linkage analysis studies aimed at the disclosure of the location of a gene on a particular chromosome used biological characteristics as genetic markers, linking their occurrence to patients with a mental disorder (Rieder and Gershon). The hope was that knowledge of the genetic locus of such a physical characteristic would eventually lead to the identification of the genetic locus for the disorder under study (Cytryn and colleagues). 

The modern techniques in molecular genetics spurred a new generation of linkage analysis studies. As it became possible to study specific DNA fragments, scientists realized that such fragments could be used as genetic markers if they showed deviations from the normal DNA sequence. In the last decade many such polymorphic DNA fragments have been isolated and identified on the human genome.

The eminently successful and almost unceasing identification of genes for numerous physical disorders serves as a powerful stimulus for comparable studies aimed at identification and localization of genes responsible for mental illness, including the affective disorders. 

While the hereditary contribution to affective disorders has been amply demonstrated by the numerous twin and adoption studies carried out in the last half-century, the exact identification of such genetic factors still remains elusive. The field of genetic inquiry of mental illness is replete with skeletons of highly publicized discoveries of genetic linkage of mental disorders that enjoyed a quick meteoric rise and an even quicker demise when the results failed to be duplicated. It is said that the euphoria of such startling discoveries gives way soon to the dysphoria of disappointment. The difficulty may possibly be related to the polygenic mode of inheritance in mental disorders (Plomin and colleagues; Reiss and colleagues). 

Other explanations focus on the interplay between inborn genetic factors and environmental influences on normal and abnormal behavior. The primacy of environmental influences in American psychiatry and psychology lasted well into the middle of this century. However, the advent of adoption and twin studies, coupled with the amazing progress in molecular genetics, led to a fascination by behavioral scientists and even the general public, which is fed an almost daily "diet" of news about important genetic discoveries in the media. Only within the last few weeks did we learn about the spectacular achievement of the team in the Institute for Genome Research led by J. Craig Venter, M.D., inventor of the gene sequencing method. In a matter of six months, researchers were able to identify the entire genome (1,700 genes) of archea, a form of life whose existence was only postulated a few years ago. 

Such recognition of hereditary factors by scientists and the general public represents, of course, a positive and long overdue development. However, this intense interest in the genetic etiology of disease has led behavioral scientists to downplay the environmental influences on human behavior. Robert Plomin, M.D., one of our eminent behavioral scientists, states it succinctly: 

"Genetic research provides the best evidence for the importance of nonheritable factors. As convincing as twin and adoption studies are, the genetic factors do not account for more than about half of the variance for behavioral disorders"and most of the disorders"show as much nonheritable as heritable influences"The current enthusiasm for genetics should not obscure the important nonheritable factors, even though they are much more difficult to investigate." 

 In a pioneering study of 680 female homozygous and heterozygous twins, Kendler and associates found that the strongest predictors of liability to major depression were, in descending order: (1) stressful life events, (2) genetic factors, (3) previous history of major depression and (4) neuroticism. The authors concluded that major depression is a multifactorial disorder, and understanding its etiology will require the rigorous interaction of genetic, temperamental and environmental risk factors. 

The many unresolved issues in behavioral genetics relates mainly to the fact that research methodology has lagged behind boldly expressed hypotheses"only by learning to use integrated, multifactorial etiological research designs will we get closer to unraveling the many causal pathways to affective disorders"(Cytryn and McKnew) 

Not until the pioneering discovery of the limbic lobe by Paul Broca in 1878 was the centrality of the brain in human behavior gradually recognized and accepted. Aristotle, widely regarded as the father of Western biology, believed that the heart is the center of sense and feeling while the brain only cools and moderates the heart. 

The recent emergence of the novel science of brain imaging permits a detailed visualization of brain structures and their function in vivo. The field can be divided into three major areas: (1) the structural examination of the brain, (2) the evaluation of brain function and (3) visualization of molecular brain structures such as receptors and neurotransmitters. 

This beginning of our "window into the brain" started with the invention of computerized axial tomography (CT scan) in 1973. This was followed in the 1980s by the introduction of magnetic resonance imaging (MRI), which offers several advantages over CT, namely, no ionizing radiation and better quality imaging without the use of contrast injections. Brain activity is being investigated chiefly by positron emission tomography (PET) and single photon emission tomography (SPECT), both of which measure cerebral blood flow as an index of brain activity. 

PET scanning also enables us to visualize neuroreceptors in vivo in the human brain. The distribution and number of specific receptors in the CNS, concentration of neurotransmitters at the synapse and the affinity of a receptor for a specific drug represent some promising areas of research which will greatly enhance our knowledge of brain neurochemistry in healthy and mentally disordered people. 

 In the psychiatric office of the future, the patient with an affective disorder is likely to be referred to a radiologist to determine his or her structural and functional brain characteristics, including the localization of brain activity, the status of neuroreceptors, neuronal cell structure and neurotransmitter distribution. Genetic testing of the patient and his close family members will follow. 

Such neurobiological analysis will help pinpoint the exact nature of the presenting disorder and facilitate a targeted, precise choice of therapeutic intervention, be it pharmacological or psychotherapeutic. 

Recent biological advances lead many to believe that the future of psychiatry depends solely on neuroscientific progress. Such views are shortsighted and fail to encompass the complexity of human behavior. Rather, the mental health clinic of the future will also offer a choice of proven psychotherapeutic modalities, social skills training, crisis intervention, divorce and grief counseling, parent and teacher effectiveness training, and other modalities aimed at strengthening the emotional resilience of patient and family. Such a comprehensive biopsychosocial approach will ensure the necessary

Dr. Cytryn is clinical professor at George Washington University Medical School. He collaborated with Donald H. McKnew Jr., M.D., on 

Growing Up Sad: Childhood Depression and Its Treatment, 

 Asarnow JR, Carlson GA, Perdue S, et al. Childhood-onset of depressive disorders: A follow-up study of rates of rehospitalization and out-of-home placement among child psychiatric inpatients. J Affect Disord. 1988;15:245-253. 
 

 Cytryn L, McKnew DH. Affective disorders in childhood. In: Kaplan HI, Friedman AM, Sadock BH, eds. Comprehensive Textbook of Psychiatry II, Vol.  III. Baltimore: Williams & Wilkins; 1980. 
 

 Cytryn L, McKnew DH, Zahn-Waxler C, et al. Developmental issues in risk research: The offspring of affectively ill parents. In: Rutter M, Izard CE, Read PB, eds. Depression in Young People: Clinical and Developmental Perspectives. New York: Guilford Press; 1986. 
 

 Kendler KS, Kessler RC, Neale MC, et al. The prediction of major depression in women: Toward an integrated etiologic model. Am J Psychiatry. 1993;150:1139-1148. 
 

 Kovacs M, Feinberg TL, Crouse-Novak MS, et al. Depressive disorders in childhood, II. A longitudinal study of the risk for a subsequent major depression. Arch Gen Psychiatry. 1984;41:643-649. 
 

 Plomin R, Owen MJ, McGuiffin P. The genetic basis of complex behavior. Science. 1994;264:1733-1739. 
 

 Reiss D, Plomin R, Hetherington EM. Genetics and psychiatry: An unheralded window on the environment. Am J Psychiatry. 1991;48:283-291. 
 

 Rieder R, Gershon ES. Genetic strategies in biological psychiatry. Arch Gen Psychiatry. 1978;35:866-873. 
 

 Weissman MM, Gammon GD, John K, et al. Children of depressed parents: Increased psychopathology and early onset of major depression. Arch Gen Psychiatry. 1987;44:847-853.

Leon Cytryn, MD

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The Cutting Edge of Sadness