Depression is a major cause of disability worldwide, but we know little about the underlying fundamental biology. Research is hindered by the difficulties of modelling a disorder of higher cognitive functions in animals. Depression can be understood as the interaction of genetic susceptibility and environmental factors; however, current classifications are purely descriptive. The complexity of this field is best approached by rigorous explorations of known candidate systems in conjunction with the use of genomic tools to discover new targets for antidepressants and to predict therapeutic outcomes.
A triad of symptoms characterizes depression: low or depressed mood, anhedonia, and low energy or fatigability. Other symptoms, such as sleep and psychomotor disturbances, pessimism, guilty feelings, low self-esteem, suicidal tendencies, and food-intake and body-weight dysregulation, are also often present. The prevalence of depression is consistently high worldwide and several lines of evidence indicate an important contribution of depression to medical morbidity
A key problem in the diagnosis of depression is the fact that the classification systems that exist today are solely based on the subjective descriptions of symptoms but there is no biological feature that separates one subtype from another. Is each subtype of depression the result of different biological abnormalities or are they different manifestations of the same underlying disease process?
A main obstacle for depression research is the fact that this condition affects higher cognitive human processes such as motivation and self-esteem, which cannot be easily modelled in animals. Although there are some animal models for depression, it is unclear whether they really model the same disorder that affects humans.
It has been proposed that understanding the pathways and mechanisms that underlie antidepressant treatments can advance our understanding of depression. Currently accepted methods of treatment include electroconvulsive therapy, cognitive-behavioral and interpersonal psychotheraphy, and pharmacological treatments that affect biogenic-amine-dependent neurotransmission. Indeed, one of the cornerstones of research on depression has been the so-called monoamine hypothesis, which invokes imbalances in monoamine brain systems as a cause of depression.
Other factors have also been implicated in the appearance of depression, but it is still a matter of debate whether they are causally involved in the pathology. They include alterations of the hypothalamus-pituitary-adrenal axis, circadian disturbances, infectious agents such as the Borna-disease virus, and neuroimmune mediators. In addition, a genetic component seems to be involved in the disease but the evidence in support of this idea is still incomplete.
Pharmacogenetic and pharmacogenomic approaches might lead to newer, more effective solutions to the problem of depression. For example, pharmacogenetic strategies that lead to the identification of the best antidepressant drug on the basis of the genetic profile of each patient would be of great value. However, research on this area is fraught with complex issues that require careful consideration.
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We are grateful to Kevin Kelly. J.L. is supported by grants from the National Institutes of Health and by awards from the Dana and Stanley Foundations. M.-L.W. is supported by a grant from the National Institutes of Health and by a NARSAD award.
American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders Fourth Edition.
A mild form of bipolar disorder, characterized by recurring episodes of hypomania and depression.
Loss of interest or pleasure in almost all activities.
The incidence or prevalence of a disease in a population.
- LEARNED HELPLESSNESS
A cessation of the attempts to reach a goal as a consequence of the idea that rewards are not contingent on the attempts. Learned helplessness is accompanied by motivational and emotional deficits that have been proposed to model certain aspects of depression.
- COGNITIVE–BEHAVIOURAL PSYCHOTHERAPY
Form of psychotherapy that aims to strengthen self-esteem and provide the patient with support and understanding. Cognitive–behavioural psychotherapy emphasizes the analysis of the problems at hand, and the definition of concrete goals and solutions so that the patient can recognize progress.
- INTERPERSONAL PSYCHOTHERAPY
Form of psychotherapy used for the treatment of depression, which explores the relationships between the patient and other people, particularly around the time when the depression began, and uses the difficulties in those relationships as a treatment focus.
- MONOAMINE OXIDASE
Enzyme located on the outer mitochondrial membrane, which catalyses the hydrolysis of biogenic amines such as catecholamines and serotonin.
- TRICYCLIC DRUGS
Molecules that inhibit biogenic amine reuptake, therefore prolonging the period during which these neurotransmitters are active at the synaptic cleft.
Signalling molecule involved in the inflammatory response that can act as an endogenous pyrogen.
The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.
- DIFFERENTIAL DISPLAY
A method for the rapid, accurate and sensitive detection of altered gene expression between different cell populations. The method is based on the amplification of 3′-terminal portions of messenger RNAs and resolution of these fragments on a DNA sequencing gel, allowing for the direct comparison of most of the mRNAs between related cells.
- SERIAL ANALYSIS OF GENE EXPRESSION
A method for the analysis of gene expression that converts polyadenylated messenger RNA into complementary DNA by reverse transcription. Oligonucleotide 'tags' are then hybridized to the cDNA, ligated to form concatemers that are amplified by PCR, and finally cloned and sequenced. The number of tags present indicates the prevalence of the gene, therefore providing a quantitative profile of cellular gene expression.
- TOTAL GENE EXPRESSION ANALYSIS
A procedure that aims to elucidate entire gene expression patterns for a given tissue or cell. It requires a complex series of steps that involve multiplex PCR, complementary DNA cloning, in vitro transcription, cDNA construction, sequencing gel analysis and quantification.
- DNA MICROARRAY
Device used to interrogate complex nucleic acid samples by hybridization. Microarrays make it possible to count the number of different RNA or complementary DNA molecules that are present in the sample of interest as a preparative stage for their subsequent characterization.
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Wong, ML., Licinio, J. Research and treatment approaches to depression. Nat Rev Neurosci 2, 343–351 (2001). https://doi.org/10.1038/35072566
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