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Endogenous Depression
Endogenous Depression Daniel Wilson, MD, PhD Creighton University, Omaha, USA William Marcil Creighton University School of Medicine, Omaha, USA Fred Petty Creighton University School of Medicine, Omaha, USA ã 2007 Elsevier Inc. All rights reserved.
Introduction Significant advances have been made in recent years in treating endogeneous depression. However, about 50% of those who receive pharmacotherapy do not achieve complete recovery without further interventions. Thus, there is a significant need for continued research in this area Kupfer and Charney (2003). A gene (5-HTT) that encodes for the protein, which transports serotonin within the synaptic cleft, has two regions, the promoter and the structural regions. The promoter region has two polymorphisms, the short (s) allele, which is less efficient at transcribing the gene and the long (l) allele, which is more efficient. In a population of 1,037 cohorts who were studied longitudinally it was established that patients with two copies of the sallele were twice as likely to experience a major depression in comparison to those patients with two copies of the l-allele. The manifestation of vulnerability, however, was only evident in the context of a major stress. For example, for those patients who experienced child abuse and had at least one s-allele, the risk for depression was 63% compared to just 30% for those abused patients with the more stable l-allele. Those patients who did not experience a major stress showed no correlation between the genetic variations and the development of depression. A greater sensitivity at the level of the amygdala in response to fearful stimuli is likely the physiologic mechanism Avashalom et al (2003).
Definition Major depression is a recurrent illness that begins, on average, at approximately 29 years of age. The average number of episodes per lifetime is four. A given episode develops over several weeks and includes neurovegatative signs of insomnia, poor appetite, decreased concentration, loss of interest, and despair. The majority (80%) of episodes are associated with a stressful life event within the past 6 months. With proper intervention the condition is treatable, with approximately 50% of patients fully recovered within 6 months. Roughly 5-10% of those who initially present with depression go on to develop bipolar disorder Matthews (2000). Endogenous refers to a depression that has no clear precipitant. It is characterized by a significant lack of interest or investment in the environment, often accompanied by the loss of pleasure typically associated with activities such as eating, sex, and hobbies Klein et al (1980).
Classification As defined by Hales and others Hales et al (1994), Major Depressive Disorder (MDD) involves one or more episodes of a persistent (>2 wks) depressed mood or loss of interest. 1
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Endogenous Depression
In addition, there must be four or more of the following signs and symptoms: weight change, appetite change, sleep disturbance, fatigue or loss of energy, feelings of guilt or worthlessness, poor concentration, psychomotor agitation or retardation, suicide attempts or thoughts of death. In addition, there must be psychosocial disruption. A Major Depression must not be secondary to substance, a general medical condition, or bereavement. Moreover, it must not be in the context of schizophrenia or other psychotic illness Matthews (2000). Dysthymic Disorder is a chronic, low-grade depression characterized by a depressed mood on most days over a 2 year period, with no absence of depression for a period of two months or longer during that time. In addition, the diagnosis of dysthymic disorder requires that two or more of the following be present: appetite changes, sleep changes, low energy or fatigue, low self-esteem, poor concentration, difficulty making decisions, and feelings of hopelessness. There must be psychosocial dysfunction and the absence of a major mental illness such as Major Depression, Bipolar Disorder, or Schizophrenia. Also, the condition must not be due to substance or a general medical condition Matthews (2000). Depressive Disorder not otherwise specified (NOS) is applied to those who do not meet the criteria for major depression, dysthymia, or adjustment disorder Matthews (2000). Adjustment Disorder with depressed mood is characterized by the symptoms of depression that do not meet the criteria for another diagnosis and is a condition that stems directly from a psychosocial stress event such as termination of a romantic relationship. It must ensue within 3 months of the stress event and usually resolves within 6 months after the event. It is not the same as bereavement Hales et al (1994). Specifiers for Major Depression (MDD) include MDD with psychotic features, MDD with melancholic features, MDD with atypical features, MDD with postpartum onset, MDD with seasonal pattern, and MDD with catatonic features Matthews (2000). Melancholia is a severe depression most likely to be found in elderly patients. Psychotic depression refers to severe depression with psychosis and is more likely in the elderly. Reversed diurnal patterns of vegetative symptoms (oversleeping, overeating, and weight gain) with prominent anxiety symptoms may be more prevalent in women than men and are characteristic of MDD with atypical features Matthews (2000). Depression may be caused by general medical conditions or medications. Examples include depressive syndromes associated with dominant hemispheric strokes, hypothyroidism, Cushing’s disease, and pancreatic cancer. Among medications, antihypertensives and oral contraceptives are among the most frequent iatrogenic causes of depression Matthews (2000).
Consequences The World Health Organization (WHO) reported in 1996 that 15% of all disability was due to depression. The WHO estimates that by 2020 depression will be the second leading cause of disease in the world. Depression that is neither detected nor treated adequately contributes to a more refractory clinical course. As less than 50% of treated cases achieve remission, the chronic cases in the community increase arithmetically. The transformation from acute to chronic is believed to be due to the lack of neuroprotective activity that is replaced with neuronal atrophy and cell death. The vicious cycle that is established is recurrences, cycle acceleration, and increasing severity. Thus, there is now a greater emphasis on early detection and treatment of this condition Greden (2003). Suicide is the most catastrophic outcome for depression. About 10–15% of patients formerly hospitalized with depression commit suicide. For every successful attempt, 18 are unsuccessful Perlis and Stern (2000).
Endogenous Depression
In 1990, the economic cost of depression in the United States was between $43.7 billion and $52.9 billion. Adjusting for inflation, the current annual estimate would be close to $70 billion Greenberg et al (2003).
Associated Disorders Depression is often seen in combination with physical diseases such as diabetes, hyperthyroidism, hypothyroidism, and Addison’s disease. In cases such as these, the physical condition may be an etiologic factor for the depression Matthews (2000). In other instances, such as with arthritis, hypertension, back pain, and heart problems, the stress associated with the physical event my precipitate episodes of depression Greenberg et al (2003). Substance use disorders are often associated with mood disorders and complicate the clinical course, as does depression in combination with dysthymia. The combination of depression with dysthymia, or double depression, has a poor prognosis Matthews (2000). Dementia often precipitates an episode of depression, which is likely due to the enhanced vulnerability to stress due to the cognitive impairment associated with dementia. The same is true of Attention-Deficit/Hyperactivity Disorder where the vulnerability to stress is consequence of a low frustration tolerance. Adjustment disorder may progress to depression given the role of stress in the etiology of this condition Matthews (2000).
Etiology The diathesis/stress concept posits that individuals vary in their risk for developing depression and that the precipitant for the condition is a stress event. A stress can be external, such as psychosocial events or internal, such as physiological events including menopause, hypothyroidism, or Parkinson’s disease. Examples of diathesis include a genetic vulnerability or negative early life experiences, such as sexual abuse and parental discord. Social learning paradigms are thought to be the mechanism for bestowing depression from parents to children. In addition, personality traits, such as neuroticism, confer a risk for depression Willner and Mithchell (2002). Genetic vulnerabilities underlie the risk for depression. Stress events induce parallels in gene expression that lead to a cascade of cellular changes associated with depression. Thus, the genetic vulnerability plays into the stress event vulnerability such that, over time, less stress is needed to induce a recurrence of depression Greden (2003). Depressive disorder is 2-4 times more prevalent among first-degree relatives of patients with mood disorders than with others. Concordance for mood disorder is greater in monozygotic than dizygotic twins by a factor of 2:1. This is also true of monozygotic twins that have been adopted. More heritable risk is associated with more severe, recurrent, or psychotic forms of mood disorders. Moreover, those at greater heritable risk are more vulnerable to stressful life events Matthews (2000).
Epidemiology The lifetime prevalence of major depressive disorder in the United States in those over 18 years of age is 10-25% for women and 5-12% for men. The point prevalence is 5-9% in women and 2-3% in men Matthews (2000).
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Endogenous Depression
Pathophysiology Data suggest that a diminished production of brain derived neurotrophic factor (BDNF) in limbic brain regions may contribute to the development of depression. Norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), and electroconvulsive seizures all appear to activate CREB-mediated expression of this peptide with a time course that parallels the clinical response to these antidepressant therapies Manji et al (2003). A reduced glial density, especially of astrocytes, is a common neuropathological finding in depression. This pathology is localized to the anterior cingulate cortex, the hippocampus, and subcortical structures. Thus, there may be monoaminergic and glial components to this illness, as well as a disruption in neurocircuitry Harrison (2002). Stress and mood disorders are thought to impair neuronal structure by increasing excitatory amino acid neurotrasmitter receptor activity with consequent neuronal damage and by down-regulation of cell surface glucose transporters. Moreover, stress and mood disorders decrease the levels of brain derived neurotrophic factor (BDNF) and decrease glial cell number, reducing a source of energy for neurons and impairing further glutamatergic neurotransmission Manji et al (2003). Brain damage resulting from stress is thought to be due, in part, to activation of the hypothalamic pituitary adrenal axis (HPA). As corticotropin releasing hormone (CRH) is associated with cognitive impairment and the progressive loss of hippocampal CA3 neurons in depressin, the CRH-1 receptor has become a target for the development of anxiolytics and antidepressants Manji et al (2003). Decreased hippocampal glucocorticoid receptor (GR) number is related to hyperactivity of the HPA axis and a cognitive impairment that is reversed by mifepristone, a GR antagonist. It is also thought that excess glucocorticoid is associated with the enhanced vulnerability of neurons to death brought on by impaired glucose metabolism, ischemia, or excessive release of excitatory amino acids Manji et al (2003). The microscopic damage associated with depression is thought to lead to impairments in brain circuitry Manji et al (2003). Another neurotransmitter implicated in depression is the peptide Substance P, a neurokinin-1 receptor agonist. Antagonists for this site are under investigation as antidepressants.
Signs and Symptoms Symptoms commonly associated with depression are persistent sadness or despair, insomnia, decreased appetite, psychomotor retardation, anhedonia, irritability, apathy or poor motivation, withdrawal, hopelessness, poor self-esteem or feelings of helplessness, and suicidal ideation.
Standard Therapies Pharmacological management of depression is effective in approximately 50-70% of patients. Agent Name
Discussion
Fluoxetine
Fluoxetine, a selective serotonin reuptake inhibitor, is a drug of choice for treating endogenous depression. Side effects associate with this agent
Endogenous Depression include nausea, diarrhea, headache, tremor, sedation, sexual dysfunction, nervousness, and insomnia. Sertraline Sertraline, a selective serotonin reuptake inhibitor, is effective in the treatment of endogenous depression. Paroxetine Paroxetine, a selective serotonin reuptake inhibitor, is effective in the treatment of endogenous depression. Citalopram Citalopram, a selective serotonin reuptake inhibitor, is effective in the treatment of endogenous depression. The L-isomer of this compound, escitalopram, is more potent and displays fewer side effects than citalopram. Fluvoxamine Fluvoxamine, a selective serotonin reuptake inhibitor, is approved for use in the treatment of OCD, but is employed for the management of endogenous depression as well. Nortriptyline Nortriptyline is a tricyclic antidepressant. The tricyclic antidepressants are thought by some to be more effective than other therapies in the treatment of melancholic and psychotic depression. As nortriptyline displays less anticholinergic and alpha-1-adrenoceptor blocking activity as compared to other members of this class, side effects are less prominent. Amitriptyline While amitriptyline, a tricyclic antidepressants, is effective in the management of endogenous depression, it is used primarily as an analgesic and under certain circumstances. Imipramine Imipramine, a tricyclic antidepressants, is effective in the management of endogenous depression. Phenelzine Phenelzine is an irreversible monoamine oxidase inhibitor. This class is thought to be particularly effective for the treatment of atypical depression with severe anxiety. However, use of this chemical class is limited because of the side effects, particular the potential for hypertensive crises, associated with it. Bupropion Buproprion is a selective inhibitor of dopamine reuptake. It may be preferentially effective for atypical and bipolar depression. While buproprion is well tolerated, it does lower the seizure threshold. It is employed as an antidepressant and to assist in smoking cessation. Venlafaxine Venlafaxine inhibits the reuptake of both serotonin and norepinephrine. It is thought to be of particular benefit in refractory cases of depression. Nefazadone Nefazadone is an inhibitor of serotonin reuptake and serotonin receptors. It is used in the treatment of endogenous depression. Mirtazapine Mirtazapine is an antagonist at 5-HT2 and 5-HT3 and an inhibitor of serotonin and norepinephrine reuptake. More, mertazapine is a potent histamine H1 receptor antagonist, making it more sedating than some other antidepressants, such as the serotonin reuptake inhibitors. Desipramine Desipramine is a tricyclic antidepressant that is effective in the treatment of endogenous depression. Clomipramine Clomipramine is a tricyclic antidepressant, with some selectivity for serotonin reuptake as compared to norepinephrine transport. While effective in the management of endogenous depression, it is most commonly used for the treatment of obsessive-compulsive disorder. Electroconvulsive ECT is generally reserved for complicated depressions, including medication Therapy (ECT) refractory cases, depression with psychosis, for patients with a high risk of suicide, when there has been a severe weight loss, and for those who have responded well to this therapy in the past. Psychotherapy While Cognitive Behavioral Therapy has been suggested to be as effective as antidepressants for treating mild to moderate depression, medication must be employed for acute depression and for inpatient treatment. Cognitive Behavioral Therapy attempts to target negative emotion by changing basic cognitive distortions. Interpersonal Therapy focuses on interpersonal role disputes, transitions, social isolates, and social skills as key factors in the evolution of depression. Combination It has been reported that interpersonal therapy may have preferential benefit in psychotherapy the areas of mood, suicidal ideas and lack of interest, while antidepressants and antidepressant have preferential benefits with regard to appetite and sleep disturbances. treatment Moreover, pharmacotherapy may have a more rapid onset of action than psychotherapy. Thus, the combination of the two may be of particular benefit in many patients.
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Endogenous Depression
Experimental Therapies Numerous approaches are being taken in an attempt to develop novel medications for the treatment of endogenous depression. Agent Name
Discussion
MK-869 CP-154526, DMP-696, CRA 1000 and CRA 1001 Duloxetine
MK-869 is a substance P neurokinin-1 receptor antagonist. These agents are corticotropin releasing hormone receptor-1 antagonist. Duloxetine inhibits the reuptake of both serotonin and norepinephrine. Reboxetine is a selective inhibitor of norepinephrine reuptake. MK-801 and ketamine are noncompetitive NMDA receptor antagonists that display antidepressant-like activity in animal models. AP-7 is a competitive NMDA receptor antagonist. LY392098 and CX516 are AMPA receptor potentiators (ARP) that increase expression of BDNF in brain. Lamotrigine is reported to be effective in the treatment of bipolar depression. Riluzuole, a benzothiazole, is an anticonvulsant and neuroprotectant. It is thought to act by inhibiting glutamateric activity in brain. Felbamate is an anticonvulsant agent. It is a noncompetitive NMDA receptor antagonist, and an inhibitior of AMPA/kainite and dihydropyridine-sensitive calcium channels. It may also increase GABA-A receptor activity. Memantine is an anticonvulsant agent thought to act, at least in part, through the glutamate system. Ketoconazole is an antifunal agent and glucocorticoid synthesis inhibitor. Mifepristone is a glucocorticoid receptor antagonist. It may be of particular value in treating psychotic depression. Antalarmin is a corticotropin-releasing hormone antagonist. PDE4 is an inhibitor of phosphodiesterase that enhances the expression of BDNF. It has displayed antidepressant-like effects in animal models. Rolipram is an inhibitor of phosphodiasterase that enhances the expression of BDNF. BDNF is a neurotropic factor thought to be important in repairing brain abnormalities responsible for depression. Pramipexole increases the production of the apoptotic neuroprotective protein bcl-2.
Reboxetine MK-801 and Ketamine
AP-7 LY392098 and CX516 Lamotrigine Riluzuole
Felbamate
Memantine Ketoconazole Mifepristone Antalarmin PDE4
Rolipram Recombinant methionyl BDNF Pramipexole
Animal Models Swim-test immobility: A rodent is placed in a beaker of water and the amount of time that elapses before the animal ceases swimming is noted. Antidepressants prolong the swimming time. This test detects a wide range of antidepressants Weiss and Kilts (1998). Tail suspension test: When suspended by its tail, a mouse will automatically attempt to free itself through struggling. Antidepressants increase the amount of time a mouse will struggle when handled this way Weiss and Kilts (1998). Chronic mild stress model: Rats are exposed to mild stressors, such as uncontrollable footshock, cold swim, change in housing condition, change of food availability, over
Endogenous Depression
several weeks. A change in open field activity that is observed in the stressed animals is reversed by antidepressants and ECT Weiss and Kilts (1998). Learned Helplessness mode: Rats and dogs are exposed to electric shocks they cannot control and are compared to those that receive shocks they can control. The animals with the uncontrollable shock are unable to acquire an active avoidance-escape response and lose weight. Antidepressants reverse these symptoms in these animals Weiss and Kilts (1998). Knockout mice are also being employed as animal models of human depression Willner and Mitchell (2002).
Other Information – Web Sites www.depressionalliance.org/ (Depression Alliance – UK) This site offers information about symptoms, treatments and organizations for those suffering from depression. www.depression.org (National Foundation for Depressive Illness) The goals of this site are to foster education to the public about depression, to impart information to professionals, and to translate greater public exposure into increasing resources for research. http://www.DforDepression.com This website offers self-help for the patient, facilitates correct approach by the doctor, and gives information on research. The University of New South Wales, St. Vincent’s Hospital of Sydney, and the World Health Organization collaboration center at the hospital sponsor it.
Journal Citations Harrison, P.J., 2002. The neuropathology of primary mood disorder. Brain, 125, 1428–1449. Manji, H.K., Quiroz, J.A., Sporn, J., Payne, J.L., Denicoff, K., Gray, N.A., Zarate, C.A., Charney, D.S., 2003. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficultto-Treat depression. Biological Psychiatry, 53(8), 633–763. Greden, J.F., 2003. Physical symptoms of epression: unmet needs. Journal of Clinical Psychiatry, 64, 5–11. Greenberg, P.E., Leong, S.A., Birnbaurm, H.G., Robinson, R.L., 2003. The economic burden of depression with painful symptoms. Journal of Clinical Psychiatry, 64, 17–23. Willner, P., Mitchell, P.J., 2002. The validity of animal models of predisposition to depression. Behavioral Pharmacology, 13, 169–188. Kupfer, D.J., Charney, D.S., 2003. Difficult-to-treat depression. Biological Psychiatry, 53, 633–634. Avshalom, C., Sugden, K., Moffit, T.E., Taylor, A., Craig, I.W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., Poulton, R., 2003. Science, 301, 386–389.
Book Citations Weiss, J.M., Kilts, C.D., 1998. Animal Models of Depression and Schizophrenia. Schatzberg, A.F., Nemeroff, C.B. (Ed.), Textbook of Psychopharmacology, Edition Second, pp. 89–109, The American Psychiatric Press, Inc, Washington, D.C. Perlis, R.H., Stern, T.A., 2000. Suicide. Stern, T.A., Herman, J.B. (Ed.), Psychiatry Update and Board Preparation, Edition First, pp. 409–413, The McGraw Hill Companies, Inc, New York. Matthews, J., 2000. Mood Disorders: Depression. Stern, T.A., Herman, J.B. (Ed.), Psychiatry Update and Board Preparation, Edition First, pp. 103–111, The McGraw Hill Companies, Inc, New York. Hales, R.E., et al. 1994. Adjustment Disorder. First, M.B. (Ed.), Diagnostic And Statistical Manuel of Mental Disorders, Edition Fourth, p. 623, American Psychiatric Association, Washington, DC. Klein, D.F., Gittelman, R., Quitkin, F., Rifkin, A., 1980. Diagnosis of Affect Disorders: Clinical Considerations. Klein, D.F., Gittelman, R., Quitkin, F., Rifkin, A. (Ed.), Diagnosis And Drug Treatment of Psychiatric Disorders: Adults and Children, Edition Second, pp. 233–234, Williams and Wilkins, Baltimore, MD.
7
Introduction Significant advances have been made in recent years in treating endogeneous depression. However, about 50% of those who receive pharmacotherapy do not achieve complete recovery without further interventions. Thus, there is a significant need for continued research in this area Kupfer and Charney (2003). A gene (5-HTT) that encodes for the protein, which transports serotonin within the synaptic cleft, has two regions, the promoter and the structural regions. The promoter region has two polymorphisms, the short (s) allele, which is less efficient at transcribing the gene and the long (l) allele, which is more efficient. In a population of 1,037 cohorts who were studied longitudinally it was established that patients with two copies of the sallele were twice as likely to experience a major depression in comparison to those patients with two copies of the l-allele. The manifestation of vulnerability, however, was only evident in the context of a major stress. For example, for those patients who experienced child abuse and had at least one s-allele, the risk for depression was 63% compared to just 30% for those abused patients with the more stable l-allele. Those patients who did not experience a major stress showed no correlation between the genetic variations and the development of depression. A greater sensitivity at the level of the amygdala in response to fearful stimuli is likely the physiologic mechanism Avashalom et al (2003).
Definition Major depression is a recurrent illness that begins, on average, at approximately 29 years of age. The average number of episodes per lifetime is four. A given episode develops over several weeks and includes neurovegatative signs of insomnia, poor appetite, decreased concentration, loss of interest, and despair. The majority (80%) of episodes are associated with a stressful life event within the past 6 months. With proper intervention the condition is treatable, with approximately 50% of patients fully recovered within 6 months. Roughly 5-10% of those who initially present with depression go on to develop bipolar disorder Matthews (2000). Endogenous refers to a depression that has no clear precipitant. It is characterized by a significant lack of interest or investment in the environment, often accompanied by the loss of pleasure typically associated with activities such as eating, sex, and hobbies Klein et al (1980).
Classification As defined by Hales and others Hales et al (1994), Major Depressive Disorder (MDD) involves one or more episodes of a persistent (>2 wks) depressed mood or loss of interest. 1
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Endogenous Depression
In addition, there must be four or more of the following signs and symptoms: weight change, appetite change, sleep disturbance, fatigue or loss of energy, feelings of guilt or worthlessness, poor concentration, psychomotor agitation or retardation, suicide attempts or thoughts of death. In addition, there must be psychosocial disruption. A Major Depression must not be secondary to substance, a general medical condition, or bereavement. Moreover, it must not be in the context of schizophrenia or other psychotic illness Matthews (2000). Dysthymic Disorder is a chronic, low-grade depression characterized by a depressed mood on most days over a 2 year period, with no absence of depression for a period of two months or longer during that time. In addition, the diagnosis of dysthymic disorder requires that two or more of the following be present: appetite changes, sleep changes, low energy or fatigue, low self-esteem, poor concentration, difficulty making decisions, and feelings of hopelessness. There must be psychosocial dysfunction and the absence of a major mental illness such as Major Depression, Bipolar Disorder, or Schizophrenia. Also, the condition must not be due to substance or a general medical condition Matthews (2000). Depressive Disorder not otherwise specified (NOS) is applied to those who do not meet the criteria for major depression, dysthymia, or adjustment disorder Matthews (2000). Adjustment Disorder with depressed mood is characterized by the symptoms of depression that do not meet the criteria for another diagnosis and is a condition that stems directly from a psychosocial stress event such as termination of a romantic relationship. It must ensue within 3 months of the stress event and usually resolves within 6 months after the event. It is not the same as bereavement Hales et al (1994). Specifiers for Major Depression (MDD) include MDD with psychotic features, MDD with melancholic features, MDD with atypical features, MDD with postpartum onset, MDD with seasonal pattern, and MDD with catatonic features Matthews (2000). Melancholia is a severe depression most likely to be found in elderly patients. Psychotic depression refers to severe depression with psychosis and is more likely in the elderly. Reversed diurnal patterns of vegetative symptoms (oversleeping, overeating, and weight gain) with prominent anxiety symptoms may be more prevalent in women than men and are characteristic of MDD with atypical features Matthews (2000). Depression may be caused by general medical conditions or medications. Examples include depressive syndromes associated with dominant hemispheric strokes, hypothyroidism, Cushing’s disease, and pancreatic cancer. Among medications, antihypertensives and oral contraceptives are among the most frequent iatrogenic causes of depression Matthews (2000).
Consequences The World Health Organization (WHO) reported in 1996 that 15% of all disability was due to depression. The WHO estimates that by 2020 depression will be the second leading cause of disease in the world. Depression that is neither detected nor treated adequately contributes to a more refractory clinical course. As less than 50% of treated cases achieve remission, the chronic cases in the community increase arithmetically. The transformation from acute to chronic is believed to be due to the lack of neuroprotective activity that is replaced with neuronal atrophy and cell death. The vicious cycle that is established is recurrences, cycle acceleration, and increasing severity. Thus, there is now a greater emphasis on early detection and treatment of this condition Greden (2003). Suicide is the most catastrophic outcome for depression. About 10–15% of patients formerly hospitalized with depression commit suicide. For every successful attempt, 18 are unsuccessful Perlis and Stern (2000).
Endogenous Depression
In 1990, the economic cost of depression in the United States was between $43.7 billion and $52.9 billion. Adjusting for inflation, the current annual estimate would be close to $70 billion Greenberg et al (2003).
Associated Disorders Depression is often seen in combination with physical diseases such as diabetes, hyperthyroidism, hypothyroidism, and Addison’s disease. In cases such as these, the physical condition may be an etiologic factor for the depression Matthews (2000). In other instances, such as with arthritis, hypertension, back pain, and heart problems, the stress associated with the physical event my precipitate episodes of depression Greenberg et al (2003). Substance use disorders are often associated with mood disorders and complicate the clinical course, as does depression in combination with dysthymia. The combination of depression with dysthymia, or double depression, has a poor prognosis Matthews (2000). Dementia often precipitates an episode of depression, which is likely due to the enhanced vulnerability to stress due to the cognitive impairment associated with dementia. The same is true of Attention-Deficit/Hyperactivity Disorder where the vulnerability to stress is consequence of a low frustration tolerance. Adjustment disorder may progress to depression given the role of stress in the etiology of this condition Matthews (2000).
Etiology The diathesis/stress concept posits that individuals vary in their risk for developing depression and that the precipitant for the condition is a stress event. A stress can be external, such as psychosocial events or internal, such as physiological events including menopause, hypothyroidism, or Parkinson’s disease. Examples of diathesis include a genetic vulnerability or negative early life experiences, such as sexual abuse and parental discord. Social learning paradigms are thought to be the mechanism for bestowing depression from parents to children. In addition, personality traits, such as neuroticism, confer a risk for depression Willner and Mithchell (2002). Genetic vulnerabilities underlie the risk for depression. Stress events induce parallels in gene expression that lead to a cascade of cellular changes associated with depression. Thus, the genetic vulnerability plays into the stress event vulnerability such that, over time, less stress is needed to induce a recurrence of depression Greden (2003). Depressive disorder is 2-4 times more prevalent among first-degree relatives of patients with mood disorders than with others. Concordance for mood disorder is greater in monozygotic than dizygotic twins by a factor of 2:1. This is also true of monozygotic twins that have been adopted. More heritable risk is associated with more severe, recurrent, or psychotic forms of mood disorders. Moreover, those at greater heritable risk are more vulnerable to stressful life events Matthews (2000).
Epidemiology The lifetime prevalence of major depressive disorder in the United States in those over 18 years of age is 10-25% for women and 5-12% for men. The point prevalence is 5-9% in women and 2-3% in men Matthews (2000).
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Endogenous Depression
Pathophysiology Data suggest that a diminished production of brain derived neurotrophic factor (BDNF) in limbic brain regions may contribute to the development of depression. Norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), and electroconvulsive seizures all appear to activate CREB-mediated expression of this peptide with a time course that parallels the clinical response to these antidepressant therapies Manji et al (2003). A reduced glial density, especially of astrocytes, is a common neuropathological finding in depression. This pathology is localized to the anterior cingulate cortex, the hippocampus, and subcortical structures. Thus, there may be monoaminergic and glial components to this illness, as well as a disruption in neurocircuitry Harrison (2002). Stress and mood disorders are thought to impair neuronal structure by increasing excitatory amino acid neurotrasmitter receptor activity with consequent neuronal damage and by down-regulation of cell surface glucose transporters. Moreover, stress and mood disorders decrease the levels of brain derived neurotrophic factor (BDNF) and decrease glial cell number, reducing a source of energy for neurons and impairing further glutamatergic neurotransmission Manji et al (2003). Brain damage resulting from stress is thought to be due, in part, to activation of the hypothalamic pituitary adrenal axis (HPA). As corticotropin releasing hormone (CRH) is associated with cognitive impairment and the progressive loss of hippocampal CA3 neurons in depressin, the CRH-1 receptor has become a target for the development of anxiolytics and antidepressants Manji et al (2003). Decreased hippocampal glucocorticoid receptor (GR) number is related to hyperactivity of the HPA axis and a cognitive impairment that is reversed by mifepristone, a GR antagonist. It is also thought that excess glucocorticoid is associated with the enhanced vulnerability of neurons to death brought on by impaired glucose metabolism, ischemia, or excessive release of excitatory amino acids Manji et al (2003). The microscopic damage associated with depression is thought to lead to impairments in brain circuitry Manji et al (2003). Another neurotransmitter implicated in depression is the peptide Substance P, a neurokinin-1 receptor agonist. Antagonists for this site are under investigation as antidepressants.
Signs and Symptoms Symptoms commonly associated with depression are persistent sadness or despair, insomnia, decreased appetite, psychomotor retardation, anhedonia, irritability, apathy or poor motivation, withdrawal, hopelessness, poor self-esteem or feelings of helplessness, and suicidal ideation.
Standard Therapies Pharmacological management of depression is effective in approximately 50-70% of patients. Agent Name
Discussion
Fluoxetine
Fluoxetine, a selective serotonin reuptake inhibitor, is a drug of choice for treating endogenous depression. Side effects associate with this agent
Endogenous Depression include nausea, diarrhea, headache, tremor, sedation, sexual dysfunction, nervousness, and insomnia. Sertraline Sertraline, a selective serotonin reuptake inhibitor, is effective in the treatment of endogenous depression. Paroxetine Paroxetine, a selective serotonin reuptake inhibitor, is effective in the treatment of endogenous depression. Citalopram Citalopram, a selective serotonin reuptake inhibitor, is effective in the treatment of endogenous depression. The L-isomer of this compound, escitalopram, is more potent and displays fewer side effects than citalopram. Fluvoxamine Fluvoxamine, a selective serotonin reuptake inhibitor, is approved for use in the treatment of OCD, but is employed for the management of endogenous depression as well. Nortriptyline Nortriptyline is a tricyclic antidepressant. The tricyclic antidepressants are thought by some to be more effective than other therapies in the treatment of melancholic and psychotic depression. As nortriptyline displays less anticholinergic and alpha-1-adrenoceptor blocking activity as compared to other members of this class, side effects are less prominent. Amitriptyline While amitriptyline, a tricyclic antidepressants, is effective in the management of endogenous depression, it is used primarily as an analgesic and under certain circumstances. Imipramine Imipramine, a tricyclic antidepressants, is effective in the management of endogenous depression. Phenelzine Phenelzine is an irreversible monoamine oxidase inhibitor. This class is thought to be particularly effective for the treatment of atypical depression with severe anxiety. However, use of this chemical class is limited because of the side effects, particular the potential for hypertensive crises, associated with it. Bupropion Buproprion is a selective inhibitor of dopamine reuptake. It may be preferentially effective for atypical and bipolar depression. While buproprion is well tolerated, it does lower the seizure threshold. It is employed as an antidepressant and to assist in smoking cessation. Venlafaxine Venlafaxine inhibits the reuptake of both serotonin and norepinephrine. It is thought to be of particular benefit in refractory cases of depression. Nefazadone Nefazadone is an inhibitor of serotonin reuptake and serotonin receptors. It is used in the treatment of endogenous depression. Mirtazapine Mirtazapine is an antagonist at 5-HT2 and 5-HT3 and an inhibitor of serotonin and norepinephrine reuptake. More, mertazapine is a potent histamine H1 receptor antagonist, making it more sedating than some other antidepressants, such as the serotonin reuptake inhibitors. Desipramine Desipramine is a tricyclic antidepressant that is effective in the treatment of endogenous depression. Clomipramine Clomipramine is a tricyclic antidepressant, with some selectivity for serotonin reuptake as compared to norepinephrine transport. While effective in the management of endogenous depression, it is most commonly used for the treatment of obsessive-compulsive disorder. Electroconvulsive ECT is generally reserved for complicated depressions, including medication Therapy (ECT) refractory cases, depression with psychosis, for patients with a high risk of suicide, when there has been a severe weight loss, and for those who have responded well to this therapy in the past. Psychotherapy While Cognitive Behavioral Therapy has been suggested to be as effective as antidepressants for treating mild to moderate depression, medication must be employed for acute depression and for inpatient treatment. Cognitive Behavioral Therapy attempts to target negative emotion by changing basic cognitive distortions. Interpersonal Therapy focuses on interpersonal role disputes, transitions, social isolates, and social skills as key factors in the evolution of depression. Combination It has been reported that interpersonal therapy may have preferential benefit in psychotherapy the areas of mood, suicidal ideas and lack of interest, while antidepressants and antidepressant have preferential benefits with regard to appetite and sleep disturbances. treatment Moreover, pharmacotherapy may have a more rapid onset of action than psychotherapy. Thus, the combination of the two may be of particular benefit in many patients.
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Endogenous Depression
Experimental Therapies Numerous approaches are being taken in an attempt to develop novel medications for the treatment of endogenous depression. Agent Name
Discussion
MK-869 CP-154526, DMP-696, CRA 1000 and CRA 1001 Duloxetine
MK-869 is a substance P neurokinin-1 receptor antagonist. These agents are corticotropin releasing hormone receptor-1 antagonist. Duloxetine inhibits the reuptake of both serotonin and norepinephrine. Reboxetine is a selective inhibitor of norepinephrine reuptake. MK-801 and ketamine are noncompetitive NMDA receptor antagonists that display antidepressant-like activity in animal models. AP-7 is a competitive NMDA receptor antagonist. LY392098 and CX516 are AMPA receptor potentiators (ARP) that increase expression of BDNF in brain. Lamotrigine is reported to be effective in the treatment of bipolar depression. Riluzuole, a benzothiazole, is an anticonvulsant and neuroprotectant. It is thought to act by inhibiting glutamateric activity in brain. Felbamate is an anticonvulsant agent. It is a noncompetitive NMDA receptor antagonist, and an inhibitior of AMPA/kainite and dihydropyridine-sensitive calcium channels. It may also increase GABA-A receptor activity. Memantine is an anticonvulsant agent thought to act, at least in part, through the glutamate system. Ketoconazole is an antifunal agent and glucocorticoid synthesis inhibitor. Mifepristone is a glucocorticoid receptor antagonist. It may be of particular value in treating psychotic depression. Antalarmin is a corticotropin-releasing hormone antagonist. PDE4 is an inhibitor of phosphodiesterase that enhances the expression of BDNF. It has displayed antidepressant-like effects in animal models. Rolipram is an inhibitor of phosphodiasterase that enhances the expression of BDNF. BDNF is a neurotropic factor thought to be important in repairing brain abnormalities responsible for depression. Pramipexole increases the production of the apoptotic neuroprotective protein bcl-2.
Reboxetine MK-801 and Ketamine
AP-7 LY392098 and CX516 Lamotrigine Riluzuole
Felbamate
Memantine Ketoconazole Mifepristone Antalarmin PDE4
Rolipram Recombinant methionyl BDNF Pramipexole
Animal Models Swim-test immobility: A rodent is placed in a beaker of water and the amount of time that elapses before the animal ceases swimming is noted. Antidepressants prolong the swimming time. This test detects a wide range of antidepressants Weiss and Kilts (1998). Tail suspension test: When suspended by its tail, a mouse will automatically attempt to free itself through struggling. Antidepressants increase the amount of time a mouse will struggle when handled this way Weiss and Kilts (1998). Chronic mild stress model: Rats are exposed to mild stressors, such as uncontrollable footshock, cold swim, change in housing condition, change of food availability, over
Endogenous Depression
several weeks. A change in open field activity that is observed in the stressed animals is reversed by antidepressants and ECT Weiss and Kilts (1998). Learned Helplessness mode: Rats and dogs are exposed to electric shocks they cannot control and are compared to those that receive shocks they can control. The animals with the uncontrollable shock are unable to acquire an active avoidance-escape response and lose weight. Antidepressants reverse these symptoms in these animals Weiss and Kilts (1998). Knockout mice are also being employed as animal models of human depression Willner and Mitchell (2002).
Other Information – Web Sites www.depressionalliance.org/ (Depression Alliance – UK) This site offers information about symptoms, treatments and organizations for those suffering from depression. www.depression.org (National Foundation for Depressive Illness) The goals of this site are to foster education to the public about depression, to impart information to professionals, and to translate greater public exposure into increasing resources for research. http://www.DforDepression.com This website offers self-help for the patient, facilitates correct approach by the doctor, and gives information on research. The University of New South Wales, St. Vincent’s Hospital of Sydney, and the World Health Organization collaboration center at the hospital sponsor it.
Journal Citations Harrison, P.J., 2002. The neuropathology of primary mood disorder. Brain, 125, 1428–1449. Manji, H.K., Quiroz, J.A., Sporn, J., Payne, J.L., Denicoff, K., Gray, N.A., Zarate, C.A., Charney, D.S., 2003. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficultto-Treat depression. Biological Psychiatry, 53(8), 633–763. Greden, J.F., 2003. Physical symptoms of epression: unmet needs. Journal of Clinical Psychiatry, 64, 5–11. Greenberg, P.E., Leong, S.A., Birnbaurm, H.G., Robinson, R.L., 2003. The economic burden of depression with painful symptoms. Journal of Clinical Psychiatry, 64, 17–23. Willner, P., Mitchell, P.J., 2002. The validity of animal models of predisposition to depression. Behavioral Pharmacology, 13, 169–188. Kupfer, D.J., Charney, D.S., 2003. Difficult-to-treat depression. Biological Psychiatry, 53, 633–634. Avshalom, C., Sugden, K., Moffit, T.E., Taylor, A., Craig, I.W., Harrington, H., McClay, J., Mill, J., Martin, J., Braithwaite, A., Poulton, R., 2003. Science, 301, 386–389.
Book Citations Weiss, J.M., Kilts, C.D., 1998. Animal Models of Depression and Schizophrenia. Schatzberg, A.F., Nemeroff, C.B. (Ed.), Textbook of Psychopharmacology, Edition Second, pp. 89–109, The American Psychiatric Press, Inc, Washington, D.C. Perlis, R.H., Stern, T.A., 2000. Suicide. Stern, T.A., Herman, J.B. (Ed.), Psychiatry Update and Board Preparation, Edition First, pp. 409–413, The McGraw Hill Companies, Inc, New York. Matthews, J., 2000. Mood Disorders: Depression. Stern, T.A., Herman, J.B. (Ed.), Psychiatry Update and Board Preparation, Edition First, pp. 103–111, The McGraw Hill Companies, Inc, New York. Hales, R.E., et al. 1994. Adjustment Disorder. First, M.B. (Ed.), Diagnostic And Statistical Manuel of Mental Disorders, Edition Fourth, p. 623, American Psychiatric Association, Washington, DC. Klein, D.F., Gittelman, R., Quitkin, F., Rifkin, A., 1980. Diagnosis of Affect Disorders: Clinical Considerations. Klein, D.F., Gittelman, R., Quitkin, F., Rifkin, A. (Ed.), Diagnosis And Drug Treatment of Psychiatric Disorders: Adults and Children, Edition Second, pp. 233–234, Williams and Wilkins, Baltimore, MD.
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