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References pertaining to the pathophysiological hypotheses of depression
Nat Neurosci. 2007 Sep;10(9):1089-93.
New insights into BDNF function in depression and anxiety.
Martinowich K, Manji H, Lu B.
Mood and Anxiety Program, National Institute of Mental Health, Building 35, Room
1C1004, 35 Convent Drive, MSC 3714, Bethesda, Maryland 20892-3714, USA.
The 'neurotrophin hypothesis of depression' is based largely on correlations
between stress or antidepressant treatment and down- or upregulation,
respectively, of brain-derived neurotrophic factor (BDNF). Genetic disruption of
the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB,
does not seem to cause depressive behaviors, but does hamper the effect of
antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the
sole mediator of depression or anxiety. Advances in BDNF cell biology, including
its transcription through multiple promoters, trafficking and secretion, may
provide new insights into its role in mood disorders. Moreover, as the precursor
proBDNF and the mature protein mBDNF can elicit opposite effects on cellular
functions, the impact of proBDNF and its cleavage on mood should be considered.
Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term
depression might contribute to the dichotomy of BDNF actions on behaviors
mediated by the brain stress and reward systems.
Publication Types:
Research Support, N.I.H., Intramural
Review
PMID: 17726474 [PubMed - indexed for MEDLINE]
Expert Rev Neurother. 2007 Jul;7(7):853-64.
Regulation of adult hippocampal neurogenesis: relevance to depression.
Vaidya VA, Fernandes K, Jha S.
Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Mumbai 400005,
India. vvaidya@tifr.res.in
Recent hypotheses suggest that depression may involve an inability to mount
adaptive structural changes in key neuronal networks. In particular, the addition
of new neurons within the hippocampus, a limbic region implicated in mood
disorders, is compromised in animal models of depression. Adult hippocampal
neurogenesis is also a target for chronic antidepressant treatments, and an
increase in adult hippocampal neurogenesis is implicated in the behavioral
effects of antidepressants in animal models. The 'neurogenic' hypothesis of
depression raises the intriguing possibility that hippocampal neurogenesis may
contribute to the pathogenesis and treatment of depressive disorders. While there
remains substantial debate about the precise relevance of hippocampal
neurogenesis to mood disorders, this provocative hypothesis has been the focus of
many recent studies. In this review, we discuss the pathways that may mediate the
effects of depression models and antidepressants on adult hippocampal
neurogenesis, and the promise of these studies in the development of novel
antidepressants.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17610392 [PubMed - indexed for MEDLINE]
Mol Psychiatry. 2007 Nov;12(11):988-1000. Epub 2007 Apr 24.
The immune-mediated alteration of serotonin and glutamate: towards an integrated
view of depression.
Muller N, Schwarz MJ.
Department for Psychiatry and Psychotherapy, Ludwig-Maximilians-Universitat
Munchen, München, Germany. Norbert.Mueller@med.uni-muenchen.de
Beside the well-known deficiency in serotonergic neurotransmission as
pathophysiological correlate of major depression (MD), recent evidence points to
a pivotal role of increased glutamate receptor activation as well. However, cause
and interaction of these neurotransmitter alterations are not understood. In this
review, we present a hypothesis integrating current concepts of neurotransmission
and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on
immunological alterations and alterations in brain morphology in MD. An immune
activation including increased production of proinflammatory cytokines has
repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2,
interferon-gamma, or tumor necrosis factor-alpha activate the tryptophan- and
serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states
during inflammatory somatic disorders are also associated with increased
proinflammatory cytokines and increased consumption of tryptophan via activation
of IDO. An enhanced consumption of serotonin and its precursor tryptophan through
IDO activation could well explain the reduced availability of serotonergic
neurotransmission in MD. An increased activation of IDO and its subsequent enzyme
kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an
enhanced production of quinolinic acid, a strong agonist of the glutamatergic
N-methyl-D-aspartate receptor. In inflammatory states of the central nervous
system, IDO is mainly activated in microglial cells, which preferentially
metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas
astrocytes - counteracting this metabolism due to the lack of an enzyme of this
metabolism - have been observed to be reduced in MD. Therefore the type 1/type 2
immune response imbalance, associated with an astrocyte/microglia imbalance,
leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are
further strongly involved in re-uptake and metabolic conversion of glutamate. The
reduced number of astrocytes could contribute to both, a diminished
counterregulation of IDO activity in microglia and an altered glutamatergic
neurotransmission. Further search for antidepressant agents should take into
account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might
exert antidepressant effects by acting on serotonergic deficiency, glutamatergic
hyperfunction and antagonizing neurotoxic effects of quinolinic acid.
Publication Types:
Review
PMID: 17457312 [PubMed - indexed for MEDLINE]
Eur Arch Psychiatry Clin Neurosci. 2007 Aug;257(5):300-3.
Neurogenesis and depression: what animal models tell us about the link.
Vollmayr B, Mahlstedt MM, Henn FA.
Central Institute of Mental Health, J5, University of Heidelberg, 68159 Mannheim,
Germany. barbara.vollmayr@zi-mannheim.de
There is growing evidence that stress causes a decrease of neurogenesis in the
dentate gyrus and antidepressant treatment in turn stimulates the cell
proliferation in the dentate gyrus. This has led to the hypothesis that a
decreased neurogenesis might be linked to the pathophysiology of major
depression. The article reviews the relationship of depressive-like behavior and
neurogenesis in three animal models of depression with high validity: learned
helplessness, chronic mild stress and chronic psychosocial stress of the tree
shrew. All animal models provide evidence that stress which can lead to
depressive-like behavior, in parallel causes a decrease of neurogenesis; vice
versa, antidepressant treatment is able to revert not only behavioral changes but
also to normalize neurogenesis. But the animal models argue against the notion
that decreases of neurogenesis are the cause or the consequence of
depressive-like behavior since depressive-like behavior can occur without
impairments in neurogenesis and decreasing neurogenesis does not neccessarily
lead to depressive-like behavior. This suggests that neurogenesis does not
directly control affect but is tightly connected to the modulation of affect by
stress and antidepressant measures.
Publication Types:
Review
PMID: 17401725 [PubMed - indexed for MEDLINE]
Curr Psychiatry Rep. 2006 Dec;8(6):452-7.
The interaction of serotonin transporter gene polymorphisms and early adverse
life events on vulnerability for major depression.
Vergne DE, Nemeroff CB.
Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Suite 4000 WMRB, 101 Woodruff Circle, Atlanta, GA 30322, USA.
Considerable literature supports the hypothesis of dysfunction in central nervous
system serotonergic circuits in the pathophysiology of mood disorders,
specifically major depression. Since the development of the selective serotonin
(5-HT) reuptake inhibitors, a putative role for the 5-HT transporter (SERT) in
the etiology of depression has been explored. The discovery of a functional SERT
polymorphism has provided a novel tool to further scrutinize the role of
serotonergic neurons in depression. This article reviews the burgeoning evidence
of an interaction between early life stress and an SERT polymorphism on
vulnerability to depression.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 17094925 [PubMed - indexed for MEDLINE]
Curr Opin Pharmacol. 2007 Feb;7(1):18-21. Epub 2006 Oct 17.
Role of neurotrophic factors in depression.
Castren E, Voikar V, Rantamaki T.
Sigrid Juselius Laboratory of Molecular Neuroscience, Neuroscience Center,
University of Helsinki, PO Box 56, 00014 Helsinki, Finland.
eero.castren@helsinki.fi
Major depression is associated with reduced volumes in the hippocampus and
prefrontal cortex, whereas antidepressant treatments promote several forms of
neuronal plasticity, including neurogenesis, synaptogenesis and neuronal
maturation, in the hippocampus. Several neurotrophic factors are associated with
depression or antidepressant action. Stress suppresses brain-derived neurotrophic
factor (BDNF) synthesis in the hippocampus, at least partially through a
sustained modification of chromatin structure. Essentially all antidepressant
treatments increase BDNF synthesis and signaling in the hippocampus and
prefrontal cortex. This signaling is required for the behavioral effects of
antidepressant drugs in rodents, and increased BDNF levels in the hippocampus
mimic the behavioral effects of antidepressants. However, injection of BDNF into
the mesolimbic dopamine pathway produces an opposing depression-like response.
One hypothesis emerging from these data proposes that mood disorders reflect
failed function of critical neuronal networks, whereas a gradual network recovery
through activity-dependent neuronal plasticity induces the antidepressant effect.
Neurotrophic factors themselves do not control mood, but they act as necessary
tools in the activity-dependent modulation of networks, the physiological
function of which determines how a plastic change influences mood.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 17049922 [PubMed - indexed for MEDLINE]
Trends Pharmacol Sci. 2006 Oct;27(10):539-45. Epub 2006 Aug 21.
Role of the endocannabinoid system in depression and suicide.
Vinod KY, Hungund BL.
Division of Analytical Psychopharmacology, New York State Psychiatric Institute,
NY 10032, USA.
Depression is one of the most prevalent forms of neuropsychiatric disorder and is
a major cause of suicide worldwide. The prefrontal cortex is a crucial brain
region that is thought to be involved in the regulation of mood, aggression
and/or impulsivity and decision making, which are altered in suicidality.
Evidence of the role of the endocannabinoid (EC) system in the neurobiology of
neuropsychiatric disorders is beginning to emerge. The behavioral effects of ECs
are believed to be mediated through the central cannabinoid CB1 receptor.
Alterations in the levels of ECs, and in the density and coupling efficacy of CB1
receptors, have been reported in the prefrontal cortex of depressed and alcoholic
suicide victims. These findings support our hypothesis that altered EC function
contributes to the pathophysiological aspects of suicidal behavior. Here, we
provide a brief overview of the role of the EC system in alcoholism, depression
and suicide, and discuss possible therapeutic interventions and directions for
future research.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
PMID: 16919786 [PubMed - indexed for MEDLINE]
Mol Psychiatry. 2006 Nov;11(11):984-91. Epub 2006 Aug 8.
The etiology of poststroke depression: a review of the literature and a new
hypothesis involving inflammatory cytokines.
Spalletta G, Bossu P, Ciaramella A, Bria P, Caltagirone C, Robinson RG.
Department of Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation,
Rome, Italy.
Although poststroke depression is unlikely to represent a single disorder and
numerous etiologies for different kinds of poststroke depression will likely
emerge as the result of future research, we believe that a number of poststroke
depressive disorders are likely to be the result of specific changes in brain
pathology and neurophysiology. Nevertheless, there are relatively few hypotheses
about the pathophysiology of poststroke depression. This paper, therefore,
proposes a new hypothesis for poststroke depression involving increased
production of proinflammatory cytokines resulting from brain ischemia in cerebral
areas linked to the pathogenesis of mood disorders. This paper reviews the
evidence supporting the hypothesis that proinflammatory cytokines are involved in
the occurrence of stroke as well as mood disorders linked to the brain damage.
The increased production of proinflammatory cytokines such as IL-1beta, TNF-alpha
or IL-18 resulting from stroke may lead to an amplification of the inflammatory
process, particularly in limbic areas, and widespread activation of indoleamine
2,3-dioxygenase (IDO) and subsequently to depletion of serotonin in paralimbic
regions such as the ventral lateral frontal cortex, polar temporal cortex and
basal ganglia. The resultant physiological dysfunction may lead to poststroke
depression. Future investigations may explore this hypothesis through more
extensive studies on the role of proinflammatory cytokines, such as IL-1beta,
TNF-alpha or even IL-18, in patients with poststroke depression.
Publication Types:
Review
PMID: 16894392 [PubMed - indexed for MEDLINE]
Curr Opin Psychiatry. 2006 Jan;19(1):14-8.
Depression and neurological disorders.
Benedetti F, Bernasconi A, Pontiggia A.
Department of Neuropsychiatric Sciences, Scientific Institute and University
Vita-Salute San Raffaele, Milan, Italy. benedetti.francesco@hsr.it
PURPOSE OF REVIEW: Clinical studies support a bidirectional link between
depression and neurological diseases. Here we review the most recent findings
supporting the hypothesis that major depression is a medical illness of the brain
which can be elicited by neurological illnesses. RECENT FINDINGS: In the last
year major improvements in brain-imaging techniques allowed correlations to be
demonstrated between functional and structural brain abnormalities in specific
brain areas (prefrontal cortex, hippocampus, cingulate gyrus) and the presence
and severity of affective disorders, thus suggesting a neural basis for their
onset and progression. Similar lesions, caused by neurological diseases, have
been found to correlate with the presence of depression in neurological
illnesses, but literature on the topic is still lacking. Depression in
neurological disorders responds to the same treatments available for idiopathic
major depression, but patients seem to have different sensitivities to side
effects depending on their specific neurological syndrome. Most available data
come from case reports and open trials. SUMMARY: 'Psychiatric' and 'neurologic'
depression seem to share common abnormalities in specific brain areas, but sound
brain-imaging studies of the neural correlates of depression in neurological
disorders are still lacking. Available treatments are efficacious, but no
clear-cut guidelines about the best drugs and dosages can be defined because
double-blind placebo-controlled studies are still scarce.
Publication Types:
Review
PMID: 16612173 [PubMed - indexed for MEDLINE]
Ageing Res Rev. 2005 May;4(2):141-94.
The stress system in the human brain in depression and neurodegeneration.
Swaab DF, Bao AM, Lucassen PJ.
Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The
Netherlands. d.f.swaab@nih.knaw.nl
Corticotropin-releasing hormone (CRH) plays a central role in the regulation of
the hypothalamic-pituitary-adrenal (HPA)-axis, i.e., the final common pathway in
the stress response. The action of CRH on ACTH release is strongly potentiated by
vasopressin, that is co-produced in increasing amounts when the hypothalamic
paraventricular neurons are chronically activated. Whereas vasopressin stimulates
ACTH release in humans, oxytocin inhibits it. ACTH release results in the release
of corticosteroids from the adrenal that, subsequently, through mineralocorticoid
and glucocorticoid receptors, exert negative feedback on, among other things, the
hippocampus, the pituitary and the hypothalamus. The most important
glucocorticoid in humans is cortisol, present in higher levels in women than in
men. During aging, the activation of the CRH neurons is modest compared to the
extra activation observed in Alzheimer's disease (AD) and the even stronger
increase in major depression. The HPA-axis is hyperactive in depression, due to
genetic factors or due to aversive stimuli that may occur during early
development or adult life. At least five interacting hypothalamic peptidergic
systems are involved in the symptoms of major depression. Increased production of
vasopressin in depression does not only occur in neurons that colocalize CRH, but
also in neurons of the supraoptic nucleus (SON), which may lead to increased
plasma levels of vasopressin, that have been related to an enhanced suicide risk.
The increased activity of oxytocin neurons in the paraventricular nucleus (PVN)
may be related to the eating disorders in depression. The suprachiasmatic nucleus
(SCN), i.e., the biological clock of the brain, shows lower vasopressin
production and a smaller circadian amplitude in depression, which may explain the
sleeping problems in this disorder and may contribute to the strong CRH
activation. The hypothalamo-pituitary thyroid (HPT)-axis is inhibited in
depression. These hypothalamic peptidergic systems, i.e., the HPA-axis, the SCN,
the SON and the HPT-axis, have many interactions with aminergic systems that are
also implicated in depression. CRH neurons are strongly activated in depressed
patients, and so is their HPA-axis, at all levels, but the individual variability
is large. It is hypothesized that particularly a subgroup of CRH neurons that
projects into the brain is activated in depression and induces the symptoms of
this disorder. On the other hand, there is also a lot of evidence for a direct
involvement of glucocorticoids in the etiology and symptoms of depression.
Although there is a close association between cerebrospinal fluid (CSF) levels of
CRH and alterations in the HPA-axis in depression, much of the CRH in CSF is
likely to be derived from sources other than the PVN. Furthermore, a close
interaction between the HPA-axis and the hypothalamic-pituitary-gonadal
(HPG)-axis exists. Organizing effects during fetal life as well as activating
effects of sex hormones on the HPA-axis have been reported. Such mechanisms may
be a basis for the higher prevalence of mood disorders in women as compared to
men. In addition, the stress system is affected by changing levels of sex
hormones, as found, e.g., in the premenstrual period, ante- and postpartum,
during the transition phase to the menopause and during the use of oral
contraceptives. In depressed women, plasma levels of estrogen are usually lower
and plasma levels of androgens are increased, while testosterone levels are
decreased in depressed men. This is explained by the fact that both in depressed
males and females the HPA-axis is increased in activity, parallel to a diminished
HPG-axis, while the major source of androgens in women is the adrenal, whereas in
men it is the testes. It is speculated, however, that in the etiology of
depression the relative levels of sex hormones play a more important role than
their absolute levels. Sex hormone replacement therapy indeed seems to improve
mood in elderly people and AD patients. Studies of rats have shown that high
levels of cumulative corticosteroid exposure and rather extreme chronic stress
induce neuronal damage that selectively affects hippocampal structure. Studies
performed under less extreme circumstances have so far provided conflicting data.
The corticosteroid neurotoxicity hypothesis that evolved as a result of these
initial observations is, however, not supported by clinical and experimental
observations. In a few recent postmortem studies in patients treated with
corticosteroids and patients who had been seriously and chronically depressed no
indications for AD neuropathology, massive cell loss, or loss of plasticity could
be found, while the incidence of apoptosis was extremely rare and only seen
outside regions expected to be at risk for steroid overexposure. In addition,
various recent experimental studies using good stereological methods failed to
find massive cell loss in the hippocampus following exposure to stress or
steroids, but rather showed adaptive and reversible changes in structural
parameters after stress. Thus, the HPA-axis in AD is only moderately activated,
possibly due to the initial (primary) hippocampal degeneration in this condition.
There are no convincing arguments to presume a causal, primary role for cortisol
in the pathogenesis of AD. Although cortisol and CRH may well be causally
involved in the signs and symptoms of depression, there is so far no evidence for
any major irreversible damage in the human hippocampus in this disorder.
Publication Types:
Review
PMID: 15996533 [PubMed - indexed for MEDLINE]
Neurosci Biobehav Rev. 2005;29(4-5):891-909.
Cytokines as mediators of depression: what can we learn from animal studies?
Dunn AJ, Swiergiel AH, de Beaurepaire R.
Department of Pharmacology, Louisiana State University Health Sciences Center,
P.O. Box 33932, Shreveport, LA 71130-3932, USA. adunn@lsuhsc.edu
It has recently been postulated that cytokines may cause depressive illness in
man. This hypothesis is based on the following observations: 1. Treatment of
patients with cytokines can produce symptoms of depression; 2. Activation of the
immune system is observed in many depressed patients; 3. Depression occurs more
frequently in those with medical disorders associated with immune dysfunction; 4.
Activation of the immune system, and administration of endotoxin (LPS) or
interleukin-1 (IL-1) to animals induces sickness behavior, which resembles
depression, and chronic treatment with antidepressants has been shown to inhibit
sickness behavior induced by LPS; 5. Several cytokines can activate the
hypothalamo-pituitary-adrenocortical axis (HPAA), which is commonly activated in
depressed patients; 6. Some cytokines activates cerebral noradrenergic systems,
also commonly observed in depressed patients; 7. Some cytokines activate brain
serotonergic systems, which have been implicated in major depressive illness and
its treatment. The evidence for each of these tenets is reviewed and evaluated
along with the effects of cytokines in classical animal tests of depression.
Although certain sickness behaviors resemble the symptoms of depression, they are
not identical and each has distinct features. Thus the value of sickness behavior
as an animal model of major depressive disorder is limited, so that care should
be taken in extrapolating results from the model to the human disorder.
Nevertheless, the model may provide insight into the etiology and the mechanisms
underlying some symptoms of major depressive disorder. It is concluded that
immune activation and cytokines may be involved in depressive symptoms in some
patients. However, cytokines do not appear to be essential mediators of
depressive illness.
Publication Types:
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 15885777 [PubMed - indexed for MEDLINE]
Prog Neuropsychopharmacol Biol Psychiatry. 2005 Feb;29(2):201-17. Epub 2005
Jan 25.
Erratum in:
Prog Neuropsychopharmacol Biol Psychiatry. 2005 May;29(4):637-8.
Cytokines and major depression.
Schiepers OJ, Wichers MC, Maes M.
Department of Psychiatry and Neuropsychology, Maastricht University, P.O. BOX
616, 6200 MD Maastricht, The Netherlands.
In the research field of psychoneuroimmunology, accumulating evidence has
indicated the existence of reciprocal communication pathways between nervous,
endocrine and immune systems. In this respect, there has been increasing interest
in the putative involvement of the immune system in psychiatric disorders. In the
present review, the role of proinflammatory cytokines, such as interleukin
(IL)-1, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma, in the
aetiology and pathophysiology of major depression, is discussed. The 'cytokine
hypothesis of depression' implies that proinflammatory cytokines, acting as
neuromodulators, represent the key factor in the (central) mediation of the
behavioural, neuroendocrine and neurochemical features of depressive disorders.
This view is supported by various findings. Several medical illnesses, which are
characterised by chronic inflammatory responses, e.g. rheumatoid arthritis, have
been reported to be accompanied by depression. In addition, administration of
proinflammatory cytokines, e.g. in cancer or hepatitis C therapies, has been
found to induce depressive symptomatology. Administration of proinflammatory
cytokines in animals induces 'sickness behaviour', which is a pattern of
behavioural alterations that is very similar to the behavioural symptoms of
depression in humans. The central action of cytokines may also account for the
hypothalamic-pituitary-adrenal (HPA) axis hyperactivity that is frequently
observed in depressive disorders, as proinflammatory cytokines may cause HPA axis
hyperactivity by disturbing the negative feedback inhibition of circulating
corticosteroids (CSs) on the HPA axis. Concerning the deficiency in serotonergic
(5-HT) neurotransmission that is concomitant with major depression, cytokines may
reduce 5-HT levels by lowering the availability of its precursor tryptophan (TRP)
through activation of the TRP-metabolising enzyme indoleamine-2,3-dioxygenase
(IDO). Although the central effects of proinflammatory cytokines appear to be
able to account for most of the symptoms occurring in depression, it remains to
be established whether cytokines play a causal role in depressive illness or
represent epiphenomena without major significance.
Publication Types:
Review
PMID: 15694227 [PubMed - indexed for MEDLINE]
Am J Geriatr Psychiatry. 2005 Feb;13(2):88-98.
Cerebrovascular disease and late-life depression.
Kales HC, Maixner DF, Mellow AM.
Section on Geriatric Psychiatry, University of Michigan, Ann Arbor, MI 48105,
USA. kales@umich.edu
Depression may occur as a result of vascular disease in a significant
subpopulation of elderly persons. Indirect support for vascular disease as an
underlying etiology of late-life depression includes the high rate of depression
in patients with vascular disease, the frequency of "silent stroke" and
white-matter hyperintensities in late-life depression, and the lower frequency of
positive family histories of depression in such patients. The authors evaluate
the associations of late-life depression with cerebrovascular disease by
reviewing the existing pathophysiological, prognosis, and treatment-outcomes
studies. Findings are based on review of the current literature systematically
searched in electronic databases. Review of such studies indicates a high
frequency of depression in older patients with cardiovascular and cerebrovascular
diseases, and the possibility of a bidirectional relationship between depression
and vascular disease. Studies examining patients with vascular depression have
found that such patients have different symptom profiles, greater disability, and
higher risk for poorer outcomes than those with nonvascular depression. Since the
vascular depression hypothesis was proposed as a conceptual framework, evidence
has accumulated that patients with vascular depression may have poorer outcomes
that may be related in part to executive dysfunction and consequent disability.
However, the association of vascular risk factors with geriatric depression has
not been consistent in the studies to-date. Although an association between a
subset of late-life depression and vascular disease is clear, significant gaps
remain in our understanding. Further research is needed to establish the precise
linkages and interactions between vascular disease and geriatric depression.
Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Review
PMID: 15703317 [PubMed - indexed for MEDLINE]
Pharmacopsychiatry. 2004 Nov;37 Suppl 2:S152-6.
Basic pathophysiological mechanisms in depression: what are they and how might
they affect the course of the illness?
Henn FA, Vollmayr B.
Central Institute of Mental Health, Department Psychiatry J5, D-68159 Mannheim,
Germany.
Basic pathophysiological mechanisms in affective disorders are discussed. Studies
carried out suggest that changes in neurogenesis do not underlie the behavioral
changes which lead to helplessness. Since the behavioral changes leading to
depressive or anxious behaviors are not correlated with changes in neurogenesis
it appears unlikely that a decrease in the rate of neurogenesis is the basis for
depression. A modified gene expression resulting in both functional and
structural brain changes remains the most consistent hypothesis to explain how
affective disorders may occur. An alternative candidate, synaptogenesis, appears
as a likely candidate and requires further experimental testing.
Publication Types:
Review
PMID: 15546068 [PubMed - indexed for MEDLINE]
J Affect Disord. 2004 Apr;79(1-3):81-95.
Depression and vascular disease: what is the relationship?
Thomas AJ, Kalaria RN, O'Brien JT.
Wolfson Research Centre, Department of Psychiatry and Institute for Ageing and
Health, University of Newcastle upon Tyne, Newcastle upon Tyne NE4 6BE, UK.
a.j.thomas@ncl.ac.uk
BACKGROUND: the 'vascular depression' hypothesis proposes that vascular disease
predisposes to, precipitates or perpetuates depression, and this proposal has
stimulated further research into the relationship of depression to vascular
disease. METHODS: We investigated the nature of the relationship between
depression and vascular diseases by reviewing epidemiological, clinical,
neuroimaging and neuropathology studies which have reported on the relationship
of depression to coronary artery disease, stroke disease, alterations in blood
pressure, vascular dementia, diabetes mellitus and cholesterol levels and by
reviewing potential mechanisms by which depression could be associated with
vascular diseases. RESULTS: there is abundant and increasing evidence from these
different lines of research that depression has a bidirectional association with
vascular diseases and plausible mechanisms exist which explain how depression
might increase these vascular diseases and vice versa. LIMITATIONS: this was not
a systematic review and so not every report of relevance has been included.
CONCLUSIONS: depression has a clear bidirectional relationship with vascular
diseases. Further study is needed to clarify the mechanisms involved and to
investigate the benefits of conventional and novel treatments for vascular
diseases in depressive illness.
Publication Types:
Review
PMID: 15023483 [PubMed - indexed for MEDLINE]
World J Biol Psychiatry. 2000 Jan;1(1):17-25.
Stress, depression and the activation of the immune system.
Leonard B.
Department of Pharmacology, National University of Ireland, Galway, Ireland.
Both stress and depression have been associated with impaired immune function and
increased susceptibility of the patient to infectious diseases and cancer. While
it was initially thought that the hypercorticosolaemia caused a suppression of
immune function, it is now apparent that adaptive changes result from chronic
stress and depression that lead to a hypoactivity of the glucocorticoid receptors
on immune cells and in limbic regions of the brain. Thus depression is now
thought to be associated with activation of some aspects of cellular immunity
resulting in the hypersecretion of proinflammatory cytokines and the
hyperactivity of the hypothalamic-pituitary-adrenal axis. There is also
experimental evidence to show that such immune activation induces "stress-like"
behavioural and neurochemical changes in rodents which supports the hypothesis
that the hypersecretion of proinflammatory cytokines are involved in the
pathology of depression. This review attempts to show how the immune, endocrine
and neurotransmitter systems are integrated and how the result of such
integration may be causally involved in the aetiology of depression.
Publication Types:
Review
PMID: 12607229 [PubMed - indexed for MEDLINE]
Psychopharmacol Bull. 2002 Summer;36 Suppl 2:6-23.
Recent advances in the neurobiology of depression.
Nemeroff CB.
Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322, USA. cnemero@emory.edu
Elucidation of the neurobiological basis of depression and other mood disorders
is rapidly increasing. Considerable experimental and clinical evidence supports
the fundamental roles of serotonin and norepinephrine, as well as the
interactions between these systems in the etiology of depression. Substantial
evidence has accrued, including changes in neurotransmitter and neurotransmitter
metabolite concentrations, reuptake sites, and receptors, to support the
hypothesis that alteration in neuronal serotonergic and noradrenergic function
occurs in the central nervous system of patients with major depression. Serotonin
and norepinephrine represent the major targets of current therapeutic
interventions, which may induce longer-term adaptive changes via modulation of
the activity of these neurotransmitters. In addition, two neuropeptide
neurotransmitters--substance P and corticotropin-releasing factor--have been
implicated in the pathophysiology of mood disorders. Preliminary studies have
reported the clinical efficacy of a tachykinin NK1 receptor antagonist and a CRF1
receptor antagonist in depressive disorders. Further clarification of the precise
neurobiological changes occurring in depression has implications for the use and
development of novel effective treatments for this disorder.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 12490820 [PubMed - indexed for MEDLINE]
Int J Neuropsychopharmacol. 2002 Dec;5(4):375-88.
The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans.
Wichers M, Maes M.
Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD
Maastricht, The Netherlands.
Administration of the cytokines interferon-alpha and interleukin-2 is used for
the treatment of various disorders, such as hepatitis C and various forms of
cancer. The most serious side-effects are symptoms associated with depression,
including fatigue, increased sleepiness, irritability, loss of appetite as well
as cognitive changes. However, great differences exist in the prevalence of the
development of depressive symptoms across studies. Differences in doses and
duration of therapy may be sources of variation as well as individual differences
of patients, such as a history of psychiatric illness. In addition, sensitization
effects may contribute to differential responses of patients to the
administration of cytokines. In animals administration of pro-inflammatory
cytokines induces a pattern of behavioural alterations called 'sickness
behaviour' which resembles the vegetative symptoms of depression in humans.
Changes in serotonin (5-HT) receptors and in levels of 5-HT and its precursor
tryptophan in depressed people support a role for 5-HT in the development of
depression. In addition, evidence exists for a dysregulation of the noradrenergic
system and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis in depression.
Some mechanisms exist which make it possible for cytokines to cross the
blood-brain barrier. Pro-inflammatory cytokines such as IL-1beta, IFN-alpha,
IFN-gamma and TNF-alpha affect the 5-HT metabolism directly and/or indirectly by
stimulating the enzyme indoleamine 2,3-dioxygenase which leads to a peripheral
depletion of tryptophan. IL-1, IL-2 and TNF-alpha influence noradrenergic
activity and IL-1, IL-6 and TNF-alpha are found to be potent stimulators of the
HPA axis. Altogether, administration of cytokines may induce alterations in the
brain resembling those found in depressed patients, which leads to the hypothesis
that cytokines induce depression by their influence on the 5-HT, noradrenergic
and HPA system.
Publication Types:
Review
PMID: 12466036 [PubMed - indexed for MEDLINE]
Prog Neuropsychopharmacol Biol Psychiatry. 2001 May;25(4):767-80.
The immune system, depression and the action of antidepressants.
Leonard BE.
Pharmacology Department, National University of Ireland, Galway. belucg@iol.ie
It is well established that the hypothalamic-pituitary-adrenal axis (HPA) is
activated by both external and internal stressors which result in the
hypersecretion of adrenal glucocorticoids. In major depression the prolonged
elevation of the glucocorticoid concentration leads to a desensitisation of the
central glucocorticoid receptors and probably those receptors located on
macrophages. These changes may account for the observation that many aspects of
cellular immunity are activated in depression (for example, the increased release
of pro-inflammatory cytokines from activated macrophages in the periphery and
brain, and the increased release of acute phase proteins from the liver) even
though other aspects of immunity (for example, natural killer cell activity and
T-cell replication) are depressed. It is also known that some of the
pro-inflammatory cytokines are potent activators of the HPA axis. Evidence is
provided that the consequences of the hypersecretion of glucocorticoids and
pro-inflammatory cytokines result in the malfunctioning of noradrenergic and
serotonergic neurotransmission in the brain, changes which are reflected in the
major symptoms of depression. Support for this view is provided by observations
of the effects of some of these cytokines in non-depressed individuals being
treated with pro-inflammatory and related cytokines for cancer. This has led to
the hypothesis that depression is a form of sickness behaviour which forms the
basis of the macrophage theory of depression. The review concludes with a
discussion of the role of antidepressants in attenuating the adverse effects of
glucocorticoids and pro-inflammatory cytokines on central neurotransmission.
Although the precise mechanisms whereby antidepressants these changes is
uncertain, there is evidence that they reduce the release of pro-inflammatory
cytokines from activated macrophages and thereby facilitate the feedback
inhibition of the HPA axis; this results in a reduction in the release of
glucocorticoids from the adrenal glands. In addition, many antidepressants have
been shown to increase the release of endogenous cytokine antagonists such as
interleukin-1 receptor antagonist and interleukin-10. Evidence is also presented
to show that different classes of antidepressants act as cyclooxygenase
inhibitors which, by lowering the concentration of inflammatory prostaglandins in
the brain, reduce the detrimental impact of the inflammatory changes on
neurotransmitter function. An advantage of the macrophage hypothesis is that it
extends the biogenic amine hypothesis of depression to take account of changes in
the endocrine and immune systems which also play a crucial role in the aetiology
of depression. In addition, the macrophage hypothesis may broaden the basis of
understanding the mechanism of action of antidepressants.
Publication Types:
Review
PMID: 11383977 [PubMed - indexed for MEDLINE]
Int J Neuropsychopharmacol. 2001 Mar;4(1):21-31.
Basal limbic system alteration in major depression: a hypothesis supported by
transcranial sonography and MRI findings.
Becker G, Berg D, Lesch KP, Becker T.
Neurologische Universitatsklinik Wurzburg, Germany.
georg.becker@mail.uni-wuerzburg.de
The pathogenesis of major depression (MD) remains unclear despite intensive
research in the last decades which brought up a multitude of findings
illustrating the complexity of this disorder. In this paper we will summarize the
evidence pointing towards a structural alteration of the basal limbic system in
MD and depression in Parkinson's disease (PD). Transcranial ultrasound and MRI
studies in both depressive syndromes revealed altered signal intensity of the
brainstem midline comprising fibre tracts of the basal limbic system. The
hypothesis of a structural disruption of the basal limbic system is supported by
biochemical and histopathological findings. The similarity of findings in MD and
depression in PD might reflect a relationship between MD and neurodegenerative
disorders.
Publication Types:
Research Support, Non-U.S. Gov't
Review
PMID: 11343626 [PubMed - indexed for MEDLINE]
Int J Dev Neurosci. 2001 Jun;19(3):305-12.
Changes in the immune system in depression and dementia: causal or co-incidental
effects?
Leonard BE.
Pharmacology Department, National University of Ireland, Galway, Ireland.
belucg@iol.ie
It is now widely accepted that psychological stress and psychiatric illness can
compromise immune function. Furthermore the mechanisms whereby such changes occur are probably associated with the activities of the cytokines and other
inflammatory mediators of the immune system which are known to initiate changes
in behaviour. This review aims to summarise the experimental and clinical
evidence that implicates the pro-inflammatory cytokines in the pathological
changes seen in major depression and in Alzheimer's disease (AD). In major
depression, evidence is provided to show that both activation (e.g., macrophage
activity, acute phase proteins) and inhibition (e.g., natural killer cell
activity) of the immune system occur. Many of the behavioural changes seen in
depression are simulated by three pro-inflammatory cytokines (IL-1, IL-6 and
TNF-alpha), which may produce their impact on the brain by activating
cyclooxygenase, nitric acid synthase and corticotrophin releasing factor.
Effective antidepressant treatments largely attenuate the immune changes thereby
raising the possibility that the normalisation of central biogenic amine function
that are conventionally implicated in the cause of depression may be secondary to
those of the pro-inflammatory cytokines.With respect to AD, while the cause(s)
are unknown, there is both experimental and clinical evidence to suggest that
inflammatory processes in the brain caused in particular by TNF-alpha together
with the subsequent rise in free radicals, are instrumental in causing the
pathological changes which underlie the disease. Evidence in favour of the
inflammatory hypothesis is supported by the finding that nonsteroidal
anti-inflammatory drugs slow down the progression of the disease. Although, more
research is needed into the inter-relationships between the various
pro-inflammatory cytokines and the behavioural changes invoked in major
depression and AD, the immunological hypothesis has been important in stimulating
new concepts regarding the causes of the pathological changes in these diseases
and how effective drug treatments may attenuate them.
Publication Types:
Review
PMID: 11337199 [PubMed - indexed for MEDLINE]
Peptides. 2001 May;22(5):845-51.
Corticotropin-releasing hormone in depression and post-traumatic stress disorder.
Kasckow JW, Baker D, Geracioti TD Jr.
Cincinnati VAMC, Psychiatry Service, 3200 Vine Street, Cincinnati, OH 45220, USA.
JKASCKOW@pol.net
Corticotropin-releasing hormone (CRH) has been implicated in the regulation of a
wide range of behaviors including arousal, motor function, feeding, and
reproduction. Because depressed patients are often hypercortisolemic and
intracerebroventricular administration of CRH to experimental animals produces a
syndrome reminiscent of depression, dysregulation of this compound has been
suggested to be involved in the pathogenesis of depressive and anxiety disorders.
Studies of cerebrospinal fluid CRH levels and clinical neuroendocrine tests in
patients with anxiety and affective disorders have supported this hypothesis.
This review discusses these neuroendocrine findings in melancholic and atypical
depression as well as post-traumatic stress disorder (PTSD). Overall, the data
suggest that melancholic depression is characterized by hyperactive central CRH
systems with overactivity of the pituitary-adrenal (HPA) axis. On the other hand,
atypical depression is characterized by hypoactive central CRH systems and
accompanying underactivity of the hypothalamic-pituitary-adrenal axis.
Furthermore, the neuroendocrinology of PTSD appears to be unique, in that
patients have hyperactive central CRH systems with underactivity of the
pituitary-adrenal axis.
Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11337099 [PubMed - indexed for MEDLINE]
Biol Psychiatry. 2001 Mar 1;49(5):391-404.
Glucocorticoid receptors in major depression: relevance to pathophysiology and
treatment.
Pariante CM, Miller AH.
Section of Clinical Neuropharmacology, Institute of Psychiatry, King's College
London, London, United Kingdom.
Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been
reliably observed in patients with major depression. One of the primary features
of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects
of the glucocorticoid dexamethasone on the production of adrenocorticotropic
hormone and cortisol during the dexamethasone suppression test and, more
recently, the dexamethasone--corticotropin-releasing hormone test. Because the
effects of glucocorticoids are mediated by intracellular receptors including,
most notably, the glucocorticoid receptor (GR), a number of studies have
considered the possibility that the number and/or function of GRs are reduced in
depressed patients. Moreover, whether antidepressants act by reversing these
putative GR changes has been examined. The extant literature on GR receptors in
major depression was reviewed along with studies examining the impact of
antidepressants on the GR. The data support the hypothesis that the function of
the GR is reduced in major depression in the absence of clear evidence of
decreased GR expression. The data also indicate that some antidepressants have
direct effects on the GR, leading to enhanced GR function and increased GR
expression. Hypotheses regarding the mechanism of these receptor changes involve
relevant second messenger pathways that regulate GR function. The findings
indicate that the GR is an important molecular target in major depression.
Further elucidation of the biochemical and molecular mechanisms involved in GR
changes in major depression is an exciting frontier that will no doubt lead to
new insights into the pathophysiology and treatment of affective disorders.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11274650 [PubMed - indexed for MEDLINE]
Crit Rev Neurobiol. 2000;14(1):23-45.
Impairment of GABAergic transmission in depression: new insights from
neuroimaging studies.
Sanacora G, Mason GF, Krystal JH.
Department of Psychiatry, Yale University School of Medicine, USA.
Several lines of evidence suggest that abnormalities in GABAergic
neurotransmission are associated with the neurobiology of depression. Animal
studies demonstrate that GABA agonists and antagonists can modulate commonly used behavioral models of depression and that chronic administration of antidepressant drugs induce marked changes in GABAergic function. In humans, depressed patients have lower plasma and CSF GABA concentrations than nondepressed comparison subjects. The recent discovery that several anticonvulsant and GABA-mimetic agents possess mood stabilizing and antidepressant properties has further increased interest in these findings. Novel imaging techniques now allow
investigation of the GABAergic contribution to affective disorder pathophysiology. Through the techniques of PET, SPECT, and MRS, GABAergic function can be evaluated in vivo. Preliminary studies employing these techniques are finding new evidence suggesting that GABAergic abnormalities are associated with stress, anxiety, and depression. This article reviews the existing literature investigating the possible involvement of GABA in the neurobiology of depression and briefly highlights how these novel neuroimaging techniques can be used to further assess this hypothesis.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 11253954 [PubMed - indexed for MEDLINE]
Neuropsychopharmacology. 2000 Nov;23(5):477-501.
The corticosteroid receptor hypothesis of depression.
Holsboer F.
Max Planck Institute of Psychiatry, Munich, Germany.
Signs and symptoms that are characteristic for depression include changes in the
setpoint of the hypothalamic-pituitary-adrenocortical (HPA) system, which in the
majority of these patients result in altered regulation of corticotropin (ACTH)
and cortisol secretory activity. More refined analysis of the HPA system revealed
that corticosteroid receptor (CR) signaling is impaired in major depression,
resulting among other changes, in increased production and secretion of
corticotropin-releasing hormone (CRH, also frequently abbreviated CRF) in various
brain regions postulated to be involved in the causality of depression. This
article summarizes the clinical and preclinical data, supporting the concept that
impaired CR signaling is a key mechanism in the pathogenesis of depression. Mouse
genetics, allowing for selective inactivation of genes relevant for HPA
regulation and molecular pharmacology, dissecting the intracellular cascade of CR
signaling, are the most promising future research fields, suited for identifying
genes predisposing to depression. Focusing on these two research lines may also
allow to gain insight into understanding how current antidepressants work and
further, how more specific targets for future antidepressant drugs can be
identified.
Publication Types:
Review
PMID: 11027914 [PubMed - indexed for MEDLINE]
J Clin Psychiatry. 2000;61 Suppl 6:12-7.
Evidence for a biochemical lesion in depression.
Leonard BE.
Department of Pharmacology, National University of Ireland, Galway.
The monoamine hypothesis of depression predicts an impairment in central
monoaminergic function. The lesion may comprise deficiencies in the absolute
concentrations of norepinephrine and/or serotonin (5-HT). Depletion studies have
shown a correlation between such deficiencies and depressive symptoms.
Measurement of the concentrations of the neurotransmitters and their metabolites
in cerebrospinal fluid, urine, and plasma of patients with depression has yielded
equivocal results regarding the possibility of altered metabolism of these
neurotransmitters. Other studies have investigated the possibility of altered
numbers and/or affinities of the serotonin and norepinephrine receptors and
uptake sites. For example, there is evidence for a reduction in the activity of
the serotonin reuptake transporter in patients with depression and an increase in
the density of 5-HT2 receptors in the brains of suicide victims. Similarly, in
the noradrenergic system, up-regulation of beta-adrenoceptors is consistently
observed. Most recently, attention has focused on the possibility that a lesion
may occur in the postreceptor, subcellular components of the monoamine systems,
such as the second messenger processes. Also, experimental evidence has shown
"cross-talk" between the noradrenergic and serotonergic systems. There is
therefore substantial clinical and experimental evidence that lesions in the
serotonergic and noradrenergic systems are responsible for depression and that
antidepressant treatment can reverse these alterations.
Publication Types:
Review
PMID: 10775019 [PubMed - indexed for MEDLINE]
J Clin Psychiatry. 2000;61 Suppl 6:4-6.
History and evolution of the monoamine hypothesis of depression.
Hirschfeld RM.
Department of Psychiatry and Behavioral Sciences, University of Texas Medical
Branch, Galveston 77555-0188, USA. rohirsch@utmb.edu
The symptoms of depression can be improved by agents that act by various
mechanisms to increase synaptic concentrations of monoamines. This finding led to
the adoption of the monoamine hypothesis of depression, first put forward over 30
years ago, which proposes that the underlying biological or neuroanatomical basis
for depression is a deficiency of central noradrenergic and/or serotonergic
systems and that targeting this neuronal lesion with an antidepressant would tend
to restore normal function in depressed patients. The hypothesis has enjoyed
considerable support, since it attempts to provide a pathophysiologic explanation
of the actions of antidepressants. However, in its original form it is clearly
inadequate, as it does not provide a complete explanation for the actions of
antidepressants, and the pathophysiology of depression itself remains unknown.
The hypothesis has evolved over the years to include, for example, adaptive
changes in receptors to explain why there should be only a gradual clinical
response to antidepressant treatment when the increase in availability of
monoamines is rapid. Still, the monoamine hypothesis does not address key issues
such as why antidepressants are also effective in other disorders such as panic
disorder, obsessive-compulsive disorder, and bulimia, or why all drugs that
enhance serotonergic or noradrenergic transmission are not necessarily effective
in depression. Despite these limitations, however, it is clear that the
development of the monoamine hypothesis has been of great importance in
understanding depression and in the development of safe and effective
pharmacologic agents for its treatment.
Publication Types:
Historical Article
Review
PMID: 10775017 [PubMed - indexed for MEDLINE]
Acta Psychiatr Scand. 2000 Jan;101(1):11-20.
PET measurements of brain glucose metabolism and blood flow in major depressive
disorder: a critical review.
Videbech P.
Department of Biological Psychiatry, Psychiatric Hospital in Arhus, Risskov,
Denmark.
OBJECTIVE: To show that PET investigations of brain function in patients with
major depression can contribute with valuable pathophysiological knowledge about
brain function of these states. METHODS: PET studies of cerebral blood flow or
glucose metabolism in patients with unipolar or bipolar depression were reviewed.
RESULTS: The studies have great discrepancies related to sample size, subject
selection, imaging protocol and image analysis. In spite of this shortcoming,
there is evidence that patients with major depression have reduced blood flow and
metabolism in the prefrontal cortex, particularly when they exhibit psychomotor
retardation. Abnormalities are also found in the anterior cingulate gyrus and the
basal ganglia. A few studies point to the possibility that response to
antidepressant treatment can be predicted from PET scans. CONCLUSION: This
evidence is consistent with the hypothesis that depressive symptoms are caused by
dysfunction of regions of the limbic system and the frontal lobes in close
connection with the basal ganglia.
Publication Types:
Review
PMID: 10674946 [PubMed - indexed for MEDLINE]
J Endocrinol. 1999 Jan;160(1):1-12.
The role of corticotropin-releasing factor in depression and anxiety disorders.
Arborelius L, Owens MJ, Plotsky PM, Nemeroff CB.
Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral
Sciences, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Corticotropin-releasing factor (CRF), a 41 amino acid-containing peptide, appears
to mediate not only the endocrine but also the autonomic and behavioral responses
to stress. Stress, in particular early-life stress such as childhood abuse and
neglect, has been associated with a higher prevalence rate of affective and
anxiety disorders in adulthood. In the present review, we describe the evidence
suggesting that CRF is hypersecreted from hypothalamic as well as from
extrahypothalamic neurons in depression, resulting in hyperactivity of the
hypothalamic-pituitary-adrenal (HPA) axis and elevations of cerebrospinal fluid
(CSF) concentrations of CRF. This increase in CRF neuronal activity is also
believed to mediate certain of the behavioral symptoms of depression involving
sleep and appetite disturbances, reduced libido, and psychomotor changes. The
hyperactivity of CRF neuronal systems appears to be a state marker for depression
because HPA axis hyperactivity normalizes following successful antidepressant
treatment. Similar biochemical and behavioral findings have been observed in
adult rats and monkeys that have been subjected to early-life stress. In
contrast, clinical studies have not revealed any consistent changes in CSF CRF
concentrations in patients with anxiety disorders; however, preclinical findings
strongly implicate a role for CRF in the pathophysiology of certain anxiety
disorders, probably through its effects on central noradrenergic systems. The
findings reviewed here support the hypothesis that CRF receptor antagonists may
represent a novel class of antidepressants and/or anxiolytics.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9854171 [PubMed - indexed for MEDLINE]
J Clin Psychiatry. 1998;59 Suppl 14:11-4.
Monoamine dysfunction and the pathophysiology and treatment of depression.
Charney DS.
Department of Psychiatry, Yale University School of Medicine, New Haven, Conn
06519, USA.
Alterations in noradrenergic and serotonergic function in the central nervous
system (CNS) have been implicated in the pathophysiology of depression and the
mechanism of action of antidepressant drugs. Based on changes in norepinephrine
and serotonin metabolism in the CNS, it has been postulated that subgroups of
patients with differential responses to norepinephrine and serotonin reuptake
inhibitors may exist. Alpha-methylparatyrosine (AMPT), which causes rapid
depletion of brain catecholamines, has been used as a noradrenergic probe to test
the hypothesis that changes in neurotransmission through the catecholamine system
may underlie the therapeutic response to norepinephrine reuptake inhibitors.
Brain serotonin is dependent on plasma levels of the essential amino acid
tryptophan. Rapid tryptophan depletion, in the form of a tryptophan-free amino
acid drink, has been used as a serotonergic probe to identify therapeutically
responsive subsets of patients. Using these probes, we have recently examined the
behavioral effects of reduced concentrations of brain monoamines on depressed
patients treated with a variety of serotonin selective reuptake inhibitors
(SSRIs) or the relatively norepinephrine-selective antidepressant desipramine,
during 3 different states: drug-free and depressed; in remission on
antidepressant drugs; and drug-free in remission. The results of a series of
investigations confirm the importance of monoamines in the mediation of depressed
mood, but also suggest that other brain neural systems may have more of a primary
role than previously thought in the pathophysiology of depression. Noradrenergic
and serotonergic probes may be used in time to identify subsets of depressed
patients to determine which patients might respond differentially to the new
selective norepinephrine reuptake inhibitors or SSRIs.
Publication Types:
Review
PMID: 9818625 [PubMed - indexed for MEDLINE]
Arch Gen Psychiatry. 1997 Jul;54(7):597-606.
Comment in:
Arch Gen Psychiatry. 1997 Jul;54(7):607-8.
A molecular and cellular theory of depression.
Duman RS, Heninger GR, Nestler EJ.
Department of Psychiatry, Yale University School of Medicine, Connecticut Mental
Health Center, New Haven, USA.
Recent studies have begun to characterize the actions of stress and
antidepressant treatments beyond the neurotransmitter and receptor level. This
work has demonstrated that long-term antidepressant treatments result in the
sustained activation of the cyclic adenosine 3',5'-monophosphate system in
specific brain regions, including the increased function and expression of the
transcription factor cyclic adenosine monophosphate response element-binding
protein. The activated cyclic adenosine 3',5'-monophosphate system leads to the
regulation of specific target genes, including the increased expression of
brain-derived neurotrophic factor in certain populations of neurons in the
hippocampus and cerebral cortex. The importance of these changes is highlighted
by the discovery that stress can decrease the expression of brain-derived
neurotrophic factor and lead to atrophy of these same populations of
stress-vulnerable hippocampal neurons. The possibility that the decreased size
and impaired function of these neurons may be involved in depression is supported
by recent clinical imaging studies, which demonstrate a decreased volume of
certain brain structures. These findings constitute the framework for an updated
molecular and cellular hypothesis of depression, which posits that stress-induced
vulnerability and the therapeutic action of antidepressant treatments occur via
intracellular mechanisms that decrease or increase, respectively, neurotrophic
factors necessary for the survival and function of particular neurons. This
hypothesis also explains how stress and other types of neuronal insult can lead
to depression in vulnerable individuals and it outlines novel targets for the
rational design of fundamentally new therapeutic agents.
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 9236543 [PubMed - indexed for MEDLINE]
Psychoneuroendocrinology. 1997;22 Suppl 1:S125-32.
Antiglucocorticoid therapies in major depression: a review.
Murphy BE.
Department of Medicine, McGill University Montreal, Canada.
In major depression there are two well-documented biochemical abnormalities:
hypercortisolism, and its resistance to dexamethasone suppression. It therefore
seems reasonable to see if giving drugs which interfere with cortisol
biosynthesis might bring about a remission. An open trial was begun in our
institution of 20 refractory patients with major depression. Aminoglutethimide,
metyrapone, ketoconazole or combinations of these drugs along with a maintenance
dose of cortisol were used for eight weeks. Of the 17 completers, eleven patients
were considered to have good responses and two partial responses. Four had
complete remissions lasting several years. A similar study of four patients who
received oral RU 486 also gave encouraging results. Two patients with obsessive
compulsive disorder associated with depression showed striking improvement on
aminoglutethimide combined with a serotonin re-uptake inhibitor. In addition to a
case report in 1988 by Ravaris et al. of a patient hypophysectomized for previous
Cushing's syndrome whose depression responded to ketoconazole, several other
studies over the past five years have had similar favorable results. Wolkowitz et
al. (1993) gave oral ketoconazole to 10 depressed patients for three weeks which
resulted in a significant drop in their Hamilton Depression Scale ratings.
O'Dwyer et al. (1995) conducted a placebo-controlled single-blind crossover study
using lifetyrapone and maintenance cortisol in eight inpatients for two weeks;
six responded. Thakore and Dinan (1995) studied eight inpatients using
ketoconazole for four weeks; there were five responders and three partial
responders. Anand et al. (1995) conducted a four-week double-blind trial of
ketoconazole in a single treatment-refractory patient with good results. Arana et
al. (1995) used a different approach but one which also leads to suppression of
endogenous corticosteroids-i.e. short-term dexamethasone suppression (4 mg/day
for four days). When tested at 14 days, 7/19 of the dexamethasone group had
responded well while only 1/18 of the placebo group had responded. While these
studies have shortcomings, antiglucocorticoid therapy appears to be an effective
tool in the treatment of major depression. Possible mechanisms are discussed, and
a unifying hypothesis is attempted.
Publication Types:
Review
PMID: 9264159 [PubMed - indexed for MEDLINE]
Eur Neuropsychopharmacol. 1995;5 Suppl:77-82.
The potential role of excessive cortisol induced by HPA hyperfunction in the
pathogenesis of depression.
Stokes PE.
Cornell Medical Center, White Plains, NY 10605, USA.
Prolonged hypothalamic-pituitary-adrenocortical (HPA) axis overactivity occurs at
all levels of this axis during stress in normals and some depressed patients.
This can induce enlargement of the pituitary and adrenals. Various reports showed
that cortisol can affect mood and behavior, and disrupt memory and recall. The
integrity of the hippocampus is essential for memory function and, via the high
density of its cortisol receptors, cortisol induced inhibitory feedback to the
HPA axis. Animal data suggest that over time aging and stress can permanently
downregulate hippocampal cell receptors, produce chronic hippocampal inflammation
(astroglial), and kill cells. Cushing's syndrome patients (high cortisol) show
diminished hippocampal size and verbal recall inversely related to cortisol
levels. All the above is consistent with the 'cascade hypothesis' of cortisol
induced hippocampal damage with resultant diminished inhibition to HPA
hyperactivity in a circular manner. High cortisol is associated with altered
neurotransmitter function, e.g., diminished brain serotonin synthesis, low CSF
5HIAA, and increased noradrenergic activity.
Publication Types:
Review
PMID: 8775763 [PubMed - indexed for MEDLINE]
Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11-38.
Evidence for an immune response in major depression: a review and hypothesis.
Maes M.
Department of Psychiatry, University Hospitals of Cleveland, Ohio, USA.
1. This paper reviews recent findings on cellular and humoral immunity and
inflammatory markers in depression. 2. It is shown that major depression may be
accompanied by systemic immune activation or an inflammatory response with
involvement of phagocytic (monocytes, neutrophils) cells, T cell activation, B
cell proliferation, an "acute" phase response with increased plasma levels of
positive and decreased levels of negative acute phase proteins, higher
autoantibody (antinuclear, antiphospholipid) titers, increased prostaglandin
secretion, disorders in exopeptidase enzymes, such as dipeptidyl peptidase IV,
and increased production of interleukin (IL)-1 beta and IL-6 by peripheral blood
mononuclear cells. 3. It is hypothesized that increased monocytic production of
interleukins (Il-1 beta and Il-6) in severe depression may constitute key
phenomena underlying the various aspects of the immune and "acute" phase
response, while contributing to hypothalamic-pituitary-adrenal-axis
hyperactivity, disorders in serotonin metabolism, and to the vegetative symptoms
(i.e. the sickness behavior) of severe depression.
Publication Types:
Review
PMID: 7708925 [PubMed - indexed for MEDLINE]
Clin Chem. 1994 Feb;40(2):288-95.
Role of serotonin in the pathophysiology of depression: focus on the serotonin
transporter.
Owens MJ, Nemeroff CB.
Department of Psychiatry and Behavioral Sciences, Emory University School of
Medicine, Atlanta, GA 30322.
Considerable evidence has accrued in the last two decades to support the
hypothesis that alterations in serotonergic neuronal function in the central
nervous system occur in patients with major depression. These findings include
the following: (a) reduced cerebrospinal fluid (CSF) concentrations of
5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin (5-HT) in
drug-free depressed patients; (b) reduced concentrations of 5-HT and 5-HIAA in
postmortem brain tissue of depressed and (or) suicidal patients; (c) decreased
plasma tryptophan concentrations in depressed patients and a profound relapse in
remitted depressed patients who have responded to a serotonergic antidepressant
when brain tryptophan availability is reduced; (d) in general, all clinically
efficacious antidepressants augment 5-HT neurotransmission following chronic
treatment; (e) clinically efficacious antidepressant action by all inhibitors of
5-HT uptake; (f) increases in the density of 5-HT2 binding sites in postmortem
brain tissue of depressed patients and suicide victims, as well as in platelets
of drug-free depressed patients; (g) decreased number of 5-HT transporter
(determined with [3H]imipramine or [3H]paroxetine) binding sites in postmortem
brain tissue of suicide victims and depressed patients and in platelets of
drug-free depressed patients. In our studies, this reduction in platelet 5-HT
transporter binding is not due to prior antidepressant treatment of
hypercortisolemia and is not observed in mania, Alzheimer disease, schizophrenia,
panic disorder, fibromyalgia, or atypical depression. In a pilot study, this
deficit predicted treatment response to an experimental antidepressant. These
findings support the hypothesis that alterations in 5-HT neurons play a role in
the pathophysiology of depression.
Publication Types:
Review
PMID: 7508830 [PubMed - indexed for MEDLINE]
Psychopharmacol Bull. 1992;28(3):261-74.
Neuroanatomical circuits in depression: implications for treatment mechanisms.
Drevets WC, Raichle ME.
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO
63110.
We previously investigated the functional neuroanatomy of familial pure
depressive disease (FPDD) using positron emission tomography (PET) measurements
of regional blood flow and obtained evidence that flow is increased in the left
prefrontal cortex, amygdala, and medial thalamus and is decreased in the medial
caudate. These data along with other evidence suggested that circuits involving
the prefrontal cortex, amygdala, and related parts of the striatum, pallidum, and
medial thalamus are involved in the pathophysiology of FPDD. One of these
circuits, the limbic-thalamo-cortical circuit, which includes the amygdala, the
medio-dorsal thalamus, and parts of the ventral and medial prefrontal cortex, may
be engaged in abnormal reverberatory activity that maintains the cognitive and
emotional set of depression. Using this hypothesis as a neural model to
investigate antidepressant treatment mechanisms, we review evidence that the
changes in dopaminergic, serotonergic, and noradrenergic function induced by
somatic antidepressant therapies may yield modulatory effects on
limbic-thalamo-cortical activity. We also discuss preliminary findings of
treatment-associated changes in this circuit in studies comparing PET images
acquired before and during antidepressant treatment.
Publication Types:
Review
PMID: 1480730 [PubMed - indexed for MEDLINE]
Am J Psychiatry. 1989 Mar;146(3):311-7.
Pathophysiology of HPA axis abnormalities in patients with major depression: an
update.
Kathol RG, Jaeckle RS, Lopez JF, Meller WH.
Department of Psychiatry, University of Iowa; Iowa City 52242.
Four hypotheses have been proposed to explain why nonsuppression on the
dexamethasone suppression test occurs in patients with major depression. These
include 1) increased metabolism of dexamethasone, 2) decreased sensitivity of
pituitary glucocorticoid receptors to dexamethasone, 3) hyperresponsivity of the
adrenal gland to ACTH stimulation, and 4) increased central drive of the
pituitary from hypothalamic/limbic structures that overrides the action of the
dexamethasone. A critical review of the literature suggests that the last
hypothesis is most closely supported by the data. Despite this conclusion,
factors other than depression may be involved in hypothalamic-pituitary-adrenal
axis dysfunction.
Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review
PMID: 2645793 [PubMed - indexed for MEDLINE]
Pharmacopsychiatry. 1988 Mar;21(2):76-82.
The role of corticotropin-releasing factor in the pathogenesis of major
depression.
Nemeroff CB.
Department of Psychiatry, Duke University Medical Center, Durham, North Carolina.
It is well established that corticotropin-releasing factor (CRF), a peptide
comprised of 41 amino acids, is the major physiological regulator of the
pituitary-adrenal axis by virtue of its role as the hypothalamic hypophysiotropic
hormone that modulates the secretion of adrenocorticotropin (ACTH) from the
anterior pituitary gland. In addition to its neuroendocrine role, CRF appears to
function as a neurotransmitter or neuromodulator in extrahypothalamic brain
areas. The peptide and its receptors are distributed throughout the central
nervous system (CNS), and CRF is released by depolarizing concentrations of
potassium in a calcium-dependent manner. After direct CNS administration, CRF
produces a number of behavioral and physiological effects that are reminiscent of
both an organism's response to stress and to the symptoms of patients with major
depression. These include: diminished food consumption, decreased sexual
behavior, disturbed sleep, alterations in locomotor activity and sympathetic
nervous system activation. Alterations in regional brain CRF concentration in
rats were observed after acute and chronic stress, i.e. decreased hypothalamic
and increased locus coeruleus CRF concentrations. To test the hypothesis that CRF
is hypersecreted in patients with major depression, the concentration of CRF in
cerebrospinal fluid (CSF) in drug-free depressed patients and age- and
sex-matched controles was measured in two studies. The depressed patients
exhibited a clear group-related increase in CSF CRF concentrations. To further
test this hypothesis that CRF is chronically hypersecreted in depressed patients,
the number and affinity of CRF receptors in frontal cortex was measured in a
group of suicides and age-matched controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review
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