Animal models of depression are research tools used to investigate depression and action of antidepressants as a simulation to investigate the symptomatology and pathophysiology of depressive illness or used to screen novel antidepressants. These models provide insights into molecular, genetic, and epigenetic factors associated with depression. Criteria for valid animal models include face, construct, and predictive validity. Endophenotypes, such as anhedonia, behavioral despair, changes in appetite, neuroanatomical alterations, neuroendocrine disturbances, alterations in sleep architecture, and anxiety-related behaviors, are evaluated in these models. Antidepressant screening tests are employed to assess the effects of genetic, pharmacological, or environmental manipulations. Stress models, including learned helplessness, chronic mild stress, and social defeat stress, simulate the impact of stressors on depression. Early life stress models, psychostimulant withdrawal models, olfactory bulbectomy, and genetically engineered mice contribute to a comprehensive understanding of depression's etiology and potential therapeutic interventions.
Major depressive disorder, also called "clinical depression" or often simply "depression", is a common, long-lasting and diverse psychiatric syndrome that significantly affects a person's thoughts, behavior, feelings and sense of well-being. Symptoms include low mood and aversion to activity. Depressed people may also feel sad, anxious, empty, hopeless, worried, helpless, worthless, guilty, irritable, hurt, or restless. They may lose interest in activities that once were pleasurable, experience loss of appetite or overeating, have problems concentrating, remembering details, or making decisions, and may contemplate or attempt suicide. Insomnia, excessive sleeping, fatigue, loss of energy, or aches, pains, or digestive problems that are resistant to treatment may also be present. [1]
About one in six people in the U.S. will succumb to depression at some point during their life span, [2] and according to the World Health Organization, depression is projected to reach second place as leading contributor to the global burden of disease by the year 2020. [3] The effects of current antidepressant drugs are often significantly delayed, with improvements beginning around 3–6 weeks after treatment is started. Despite the clinical success of many antidepressant drugs, such as tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and serotonin reuptake inhibitors (SRIs), many individuals' symptoms are not adequately alleviated by medication alone, and other methods of treatment may be recommended. [4] [5]
It is difficult to develop an animal model that perfectly reproduces the symptoms of depression in patients. Is generic that 3 standards may be used to evaluate the reliability of an animal version of depression: the phenomenological or morphological appearances (face validity), a comparable etiology (assemble validity), and healing similarities (predictive validity) Many animals lack self-consciousness, self-reflection, and consideration; moreover, hallmarks of the disorder such as depressed mood, low self-esteem or suicidality are hardly accessible in non-humans. However, depression, as other mental disorders, consists of endophenotypes [6] that can be reproduced independently and evaluated in animals. An ideal animal model offers an opportunity to understand molecular, genetic, and epigenetic factors that may lead to depression. By using animal models, the underlying molecular alterations and the causal relationship between genetic or environmental alterations and depression can be examined, which would afford a better insight into pathology of depression. In addition, animal models of depression are indispensable for identifying novel therapies for depression. [7]
The following endophenotypes have been described: [6]
An appropriate animal model of human depression should fulfill the following criteria as much as possible: strong phenomenological similarities and similar pathophysiology (face validity), comparable etiology (construct validity), and common treatment (predictive validity). [8] [9] [10] Again, depression is a heterogeneous disorder and its many symptoms are hard to be produced in laboratory animals. The question therefore remains whether we can know the animal is "depressed". Animals are unable to have the emotions that are associated specifically with humans, like sadness. [11] Actually, few models of depression fully fit these validating criteria, and most models currently used rely on either actions of known antidepressants or responses to stress. It is not necessary for an "ideal" animal model of depression to exhibit all the abnormalities of depression-relevant behaviors, just as not all patients manifest every possible symptom of depression.
Antidepressant screening tests, not like the models which can be defined as an [organism] or a particular state of an organism that reproduces aspects of human pathology, provide only an end-point behavioral or physiological measure designed to assess the effect of the genetic, pharmacological, or environmental manipulation.
Certain types of human depression are precipitated by stressful life events, and vulnerable individuals experiencing these stressors may develop clinical depression. Consequently, the majority of animal models of depression are based on the exposure to various types of acute or chronic stressors.
Early adverse experiences such as traumatic life events in childhood result in an increased sensitivity to the effects of stress later in life and influence the individual vulnerability to depression. [32] Suitable animal models could provide a basis for understanding potential mechanisms of environmental and developmental factors of individual differences in stress reactivity and vulnerability to disorders. Models of early life stress involve prenatal stress, early postnatal handling and maternal separation. All these treatments have been demonstrated to produce significant effects that last until adulthood.
A mood disorder, also known as an affective disorder, is any of a group of conditions of mental and behavioral disorder where the main underlying characteristic is a disturbance in the person's mood. The classification is in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD).
Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure. While earlier definitions emphasized the inability to experience pleasure, anhedonia is currently used by researchers to refer to reduced motivation, reduced anticipatory pleasure (wanting), reduced consummatory pleasure (liking), and deficits in reinforcement learning. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), anhedonia is a component of depressive disorders, substance-related disorders, psychotic disorders, and personality disorders, where it is defined by either a reduced ability to experience pleasure, or a diminished interest in engaging in previously pleasurable activities. While the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) does not explicitly mention anhedonia, the depressive symptom analogous to anhedonia as described in the DSM-5 is a loss of interest or pleasure.
Dysthymia, also known as persistent depressive disorder (PDD), is a mental and behavioral disorder, specifically a disorder primarily of mood, consisting of similar cognitive and physical problems as major depressive disorder, but with longer-lasting symptoms. The concept was used by Robert Spitzer as a replacement for the term "depressive personality" in the late 1970s.
Atypical depression is defined in the DSM-IV as depression that shares many of the typical symptoms of major depressive disorder or dysthymia but is characterized by improved mood in response to positive events. In contrast to those with atypical depression, people with melancholic depression generally do not experience an improved mood in response to normally pleasurable events. Atypical depression also often features significant weight gain or an increased appetite, hypersomnia, a heavy sensation in the limbs, and interpersonal rejection sensitivity that results in significant social or occupational impairment.
In psychology, emotional detachment, also known as emotional blunting, is a condition or state in which a person lacks emotional connectivity to others, whether due to an unwanted circumstance or as a positive means to cope with anxiety. Such a coping strategy, also known as emotion-focused coping, is used when avoiding certain situations that might trigger anxiety. It refers to the evasion of emotional connections. Emotional detachment may be a temporary reaction to a stressful situation, or a chronic condition such as depersonalization-derealization disorder. It may also be caused by certain antidepressants. Emotional blunting, also known as reduced affect display, is one of the negative symptoms of schizophrenia.
An anxiogenic or panicogenic substance is one that causes anxiety. This effect is in contrast to anxiolytic agents, which inhibits anxiety. Together these categories of psychoactive compounds may be referred to as anxiotropic compounds.
In social psychology, social defeat is the negative experience of being excluded from the majority group. The term is used in the study of the physiological and behavioral effects of hostile interactions among either animals or humans, in either a dyadic or in a group-individual context, potentially greatly affecting control over resources, access to mates, and social positions.
Psychological dependence is a cognitive disorder and a form of dependence that is characterized by emotional–motivational withdrawal symptoms upon cessation of prolonged drug use or certain repetitive behaviors. Consistent and frequent exposure to particular substances or behaviors is responsible for inducing psychological dependence, requiring ongoing engagement to prevent the onset of an unpleasant withdrawal syndrome driven by negative reinforcement. Neuronal counter-adaptation is believed to contribute to the generation of withdrawal symptoms through changes in neurotransmitter activity or altered receptor expression. Environmental enrichment and physical activity have been shown to attenuate withdrawal symptoms.
The elevated plus maze (EPM) is a test measuring anxiety in laboratory animals that usually uses rodents as a screening test for putative anxiolytic or anxiogenic compounds and as a general research tool in neurobiological anxiety research such as PTSD and TBI. The model is based on the test animal's aversion to open spaces and tendency to be thigmotaxic. In the EPM, this anxiety is expressed by the animal spending more time in the enclosed arms. The validity of the model has been criticized as non-classical clinical anxiolytics produce mixed results in the EPM test. Despite this, the model is still commonly used for screening putative anxiolytics and for general research into the brain mechanisms of anxiety.
Scientific studies have found that different brain areas show altered activity in humans with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.
The tail suspension test (TST) is an experimental method used in scientific research to measure stress in rodents. It is based on the observation that if a mouse is subjected to short term inescapable stress then the mouse will become immobile. It is used to measure the effectiveness of antidepressant-like agents but there is significant controversy over its interpretation and usefulness.
ALTO-100, previously known as NSI-189, is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD). There has also been interest in ALTO-100 for possible treatment of cognitive impairment and neurodegeneration. It is taken by mouth.
Buprenorphine/samidorphan is a combination formulation of buprenorphine and samidorphan which is under development as an add on to antidepressants in treatment-resistant depression (TRD).
Epigenetics of depression is the study of how epigenetics contribute to depression.
Marble burying is an animal model used in scientific research to depict anxiety or obsessive–compulsive disorder (OCD) behavior. It is based on the observation that rats and mice will bury either harmful or harmless objects in their bedding. While widely used there is significant controversy over the interpretation of its results.
Immuno-psychiatry, according to Pariante, is a discipline that studies the connection between the brain and the immune system. It differs from psychoneuroimmunology by postulating that behaviors and emotions are governed by peripheral immune mechanisms. Depression, for instance, is seen as malfunctioning of the immune system.
Major depression is often associated or correlated with immune function dysregulation, and the two are thought to share similar physiological pathways and risk factors. Primarily seen through increased inflammation, this relationship is bidirectional with depression often resulting in increased immune response and illness resulting in prolonged sadness and lack of activity. This association is seen both long-term and short-term, with the presence of one often being accompanied by the other and both inflammation and depression often being co-morbid with other conditions.
Epigenetics of anxiety and stress–related disorders is the field studying the relationship between epigenetic modifications of genes and anxiety and stress-related disorders, including mental health disorders such as generalized anxiety disorder (GAD), post-traumatic stress disorder, obsessive-compulsive disorder (OCD), and more. These changes can lead to transgenerational stress inheritance.
Angela J. Grippo is an American neuroscientist and health psychologist known for her research on stress, mood disorders, and cardiovascular disease. She is an associate professor of psychology at Northern Illinois University.
Adult neurogenesis is the process by which functional, mature neurons are produced from neural stem cells (NSCs) in the adult brain. In most mammals, including humans, it only occurs in the subgranular zone of the hippocampus, and in the olfactory bulb. The neurogenesis hypothesis of depression proposes that major depressive disorder is caused, at least partly, by impaired neurogenesis in the subgranular zone of the hippocampus.
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