Durer's Melancholia.	Beyond the Catecholamine Theory of Mood Author Paul Kenyon "Depression is cancer of the emotions" (Lewis Wolpert)
	Introduction Depression: The Scale of the Problem The Scale of the Prize The Catecholamine Theory of Mood Biological Markers for Depression NA metabolism and depression Pharmacological challenge with AMPT 5-HT metabolism and depression Permissive Biogenic Amine Theory Revised CA Theory of Mood	The Prozac Story Side Effects of Tricyclic Antidepressants and Prozac The Current Status of Antidepressant Drugs Role of the hypothalamus pituitary adrenal system in depression Nemeroff's Stress-Diathesis Model of Mood Disorders Fawcett's Model of Suicide References Online Resources Further reading Visit the SALMON Bookshop for recommended books on this topic	Enter your search terms Web www.flyfishingdevon.co.uk Submit search form

Introduction

This web page is designed to give a flavour of the theories that have influenced research into the biological basis of depression over the last 35 years. This is a very large topic in terms of research effort, human suffering and financial implications.

I have adopted an historical approach beginning with Schildkraut's 1965 Catecholamine Theory of Mood (this theory was covered earlier in the course ), before discussing work on biological markers which revealed the importance of serotonin (5-HT) in depression. The role of 5-HT was recognized by Prange who suggested a Permissive Biogenic Amine Theory in 1974. In the late 1970s public reaction grew as reports of the addictive potential of minor tranquillizers used to treat anxiety were published. This was fertile ground for the arrival of Prozac in 1987 which ushered in the "antidepressant decade". In the 1990s research for new antidepressant medications focussed on serotonin uptake inhibitors to rival Prozac's phenomenal success.

In 2000 some researchers believe that we have reached the end of the line in terms of developing drugs that affect serotonin. They believe that the new millennium will see drug therapies based on a completely different approach. To reflect this mood I have chosen to include Nemeroff's 1998 Stress-Diathesis Model of Mood Disorders in which he postulates that drugs which restore equilibrium in the hypothalamus-pituitary-adrenal system may be effective antidepressants.

Despite 35 years of research antidepressant drugs still

1. cause adverse side effects
2. show 'therapeutic lag'
3. only work for about 70% of patients

Depression: The Scale of the Problem

• It is estimated that 5 to 12 percent of men and 10 to 20 percent of women in the U.S. will suffer from a major depressive episode at some time in their life.
• Depression is life-threatening: about 15% of depressives commit suicide each year.
• In 1996 the Centers for Disease Control and Prevention listed suicide as the ninth leading cause of death in the U.S. (slightly behind infection with the AIDS virus), taking the lives of 30,862 people
• In 1992 the estimated costs of depression totalled $43 billion, mostly from reduced or lost worker productivity.

(Source: Nemeroff, 1998)

Depression: The Scale of the Prize

The Catecholamine Theory of Mood

A neurochemical model, often called the Catecholamine (CA) Theory of Mood was published by Schildkraut in 1965 to explain the role of monoamines in mania and depression. The theory suggests that

• depression is associated with a functional deficiency of noradrenalin (NA) at receptor sites within the brain,
• mania is associated with an excess of NA at central receptor sites.

This table summarizes the behavioural and pharmacological observations Schildkraut used to support his theory

Notes :

• reuptake refers to a mechanism that pumps neurotransmitter molecules from the synaptic cleft back into presynaptic cells
• imipramine ia a tricyclic antidepressant (TCA), so-named because they contain three rings of chemical groups
• the catecholamine theory of mood, reserpine, MAOIs and tetrabenazine are the subject of a separate lecture in this series

I have included this table because it contains several early clues to the problems that have confronted the CA theory in the last 35 years.

• If depression is simply a matter of reduced CA levels within the brain you would expect that alpha-methylparatyrosine (which inhibits tyrosine hydroxylase - the rate limiting enzyme in CA synthesis) would produce depression in humans. Alpha-methylparatyrosine does not have this effect.
• Reserpine does produce depression in some patients. Reserpine interferes with neurotransmitter storage and thereby causes depletion of monoamines (noradrenalin, dopamine and serotonin ) in the brain

The CA theory of mood dominated research in this area for several decades. Nowadays, attention is directed more broadly at the role of monamines (group name for serotonin and the catecholamines) in depression. Serotonin (5-HT), and a possible interaction between 5-HT and NA, may play an important role in mood.

 
Biological Markers for Depression

I use the term 'biological marker' to describe a biological change associated with depression that could be used to indicate the presence and severity of the condition.

There are several reasons to search for biological markers for depression.

• Depression manifests itself as a complex cognitive, motivational and emotional disorder which is hard to diagnose and is potentially life-threatening. Depression is diagnosed on the basis of a patient's behaviour, not on the basis of sending a sample for a laboratory test. The search for biological markers for depression is partially motivated by the need for a better diagnostic tool.
• Antidepressant drugs have been available for over 40 years, but they share a common property - therapeutic lag . Normally it takes 14-21 days for the patient to benefit from the drug; during this time they are at risk of suicide. A biological marker could be used to track improvement under drug treatment.
• Biological markers may give an insight into the underlying biological basis of depression which can be used to develop more effective drug treatments.

NA metabolism and depression

A number of investigators have compared neurotransmitter metabolites in normal and depressed patients. One problem is uncertainty over how much of the metabolite is derived from brain metabolism. NA is broken down by enzymes into MHPG and VMA. This table shows that VMA and MHPG may reflect NA activity in different parts of the body.

MHPG (3-methoxy-4-hydroxyphenylglycol) and Vanillymandelic acid (VMA) are produced when NA is broken down by enzymes.

• MHPG is the principal NA metabolite found in the human cerebrospinal fluid (CSF) which suggests that it may provide a good estimate of NA activity within the brain.
• Vanillymandelic acid (VMA) is the principal NA metabolite found in human urine which suggests that it may provide a good estimate of NA activity outside the brain.

Caveats : Several studies have examined the amounts of MHPG in normal and depressed patients. But these studies should be interpreted cautiously because MHPG can be generated from peripheral NA . Similarly, about 50% of CSF (cerebrospinal fluid) 5-HIAA (5-hydroxyindoleacetic acid) is the result of 5-HT metabolism in the brain
(Source: Feldman et al ( Principles of Neuropsychopharmacology , Sinauer, Massachusetts, 1997).

Schatzberg & Schildkraut (1995) conclude that MHPG levels may predict how a patient will respond to antidepressant medication.

• Patients with low MHPG levels (i.e. reduced central NA activity) respond better to tricyclic antidepressant drugs than depressed patients with higher levels of the metabolite.
• In addition MHPG level increases as these patients respond to drug therapy

(Schatzberg & Schildkraut , In Psychopharmacology: The Fourth Generation of Progress (F.E. Bloom and D.J. Kupfer, Eds.), pp911-920, Raven Press, New York, 1995)

Pharmacological challenge with AMPT

We have seen the problems associated with interpreting the contribution of central NA metabolism to MHPG levels. Recently several Investigators have used alpha-methylparatyrosine (AMPT) to test the fragility of a person's NA system. The idea behind this approach is that if the patient reacts to AMPT with an increase in depressive symptoms this may indicate that they are at risk of developing depression in the future.

AMPT inhibits the enzyme tyrosine hydroxylase and therefore produces a decline in the NA synthesis. Berman et al (1999) administered AMPT or placebo to medication-free subjects with a history of major depression. The results show that AMPT produced a significant increase in depression ( measured by Hamilton Depression Rating Scale scores). It may be possible to use pharmacological challenge with AMPT as a test to determine if a person is at risk from depression. See Csernansky & Posener (1999) for a critical review of this suggestion References: Berman et al ( Arch Gen Psychiatry 1999 May; 56(5):395-40 ) Csernansky & Posener ( Arch Gen Psychiatry 1999 May; 56(5))

5-HT metabolism and depression

One challenge thrown up by these results is the existence of depressed patients with normal levels of MHPG who do not respond well to conventional tricyclic antidepressants.

• What is the biological basis of the illness in these patients?- it does not appear to be due to a deficiency of NA activity within the brain
• How can they be treated?

Asberg (1976) has suggested that there is a bimodal distribution of the serotonin metabolite 5-HIAA in depressed patients. The diagram shows that there are significantly more patients with low 5-HIAA levels in the sample population than would be expected by chance. I have tentatively outlined the 'low-5-HIAA subgroup' in yellow This study suggests that there may be various types of depression, each characterized by a particular neurotransmitter imbalance. Reference: Asberg ( Science , 191, 478-480, 1976)

Asberg compared the 5-HIAA levels of 46 patients who had attempted suicide with 45 healthy volunteers. The most striking finding was that patients who attempted violent suicides - by hanging or drowning - had very low 5-HIAA levels compared to those who made non-violent suicide attempts. I have used the average values of normal controls to identify the 'low-5-HIAA subgroup' in the diagram above Low 5-HIAA is also associated with increased aggressive, hostile and impulsive behaviour Low 5-HIAA may be a biological marker for suicidal behaviour , rather than depression per se .

Several years ago Beckman and Goodwin suggested that patients with low MHPG levels responded to drugs that increased NA at central receptor sites. In contrast, patients with normal MHPG levels - but low 5-HIAA levels - responded to drugs that increased the level of 5-HT at receptors.( Archives of General Psychiatry , 32, 17-21, 1975)

Permissive Biogenic Amine Theory

If you step back for a moment from considering the bewildering array of research on the role of neurotransmitters in depression you become aware that one barrier to progress may be the hidden assumption that one day depression will be understood in terms of an abnormality in a single neurotransmitter system. Perhaps it is time to consider the possibility that different neurotransmitters may interact to produce depression.

There have been several attempts to propose this type of theory. For example, Prange ( Archives of General Psychiatry , 30, 65-, 1974) developed a Permissive Biogenic Amine Hypothesis of Affective Disorder which suggests that a deficit in serotonin transmission permits but does not cause affective disorder.

Changes in catecholamine transmission when they occur in the context of a serotonin deficit determine the intensity and nature of the affective disorder.

• If catecholamine activity is increased then the patient will exhibit mania .
• If catecholamine activity is decreased then the patient will exhibit depression .

Consequently depression could be treated by either treating the underlying serotonin abnormality, or by restoring NA activity to normal.

It is unlikely that this theory is correct in its present form. For example, it predicts that all depressed patient will have decreased 5-HIAA and MHPG levels, and we already know that this is not the case.

An alternative hypothesis that would be consistent with the information we have explored is that depression comes in two types. One associated with abnormal serotonin activity, the other involving noradrenalin. There are a number of drugs that selectively enhance activity in these systems which we can use to test this theory. We already know from Beckman and Goodwin's work that some patients respond better to imipramine (blocks NA uptake) whilst other patients improve on the 5-HT reuptake blocker amitriptyline.

Miller et al (Arch Gen Psychiatry, 1996 Feb, 53:2, 117-28) investigated the effect of alpha-methylparatyrosine (AMPT) on depression in patients who had been treated with either norepinephrine reuptake inhibitors, or serotonin reuptake inhibitors. AMPT inhibits the enzyme tyrosine hydroxylase and therefore produces a decline in the CA synthesis. This leads to a reduction in production of the CA metabolite MHPG.

The therapeutic effects of norepinephrine reuptake inhibitors, but not serotonin reuptake inhibitors, are reversed by catecholamine depletion. These results suggest that antidepressants may not work via a single monoamine-related mechanism.

Revised CA Theory of Mood

Nowadays nobody would advocate a single-transmitter theory of mood (e.g. the CA theory of mood). Instead theoretical debates are dominated by the monoamine hypothesis of depression which proposes that the biological basis for depression is a deficiency in the neurotransmitters serotonin or noradrenaline, or both. The s elective s erotonin r euptake i nhibitors(SSRIs) e.g. fluoxetine (Prozac) have made a significant contribution to our understanding of the role of serotonin in depression.

The Prozac Story  

We have already examined some of the experimental findings that led to a broadening of the original CA theory to include 5-HT. But you should also be aware that theoretical advances are often facilitated or hindered by the tools available for exploring transmitters in the brain. For example, one impetus to work on serotonin was the arrival 10 years ago of drugs like Prozac that specifically blocked 5-HT reuptake. This means that scientists had a 'clean' tool to investigate the role of serotonin in behaviour. In contrast there are fewer techniques available to cleanly investigate the role of NA. For example, reboxetine, the first selective noradrenaline reuptake inhibitor, has only recently synthesized. Consequently we may soon see attention refocused on the role of noradrenaline in depression. (Racagni and Brunello, Int Clin Psychopharmacol 1999 May; 14 Suppl 1:S3-7) Prior to the introduction of Prozac, pharmaceutical companies had been quite successful in synthesizing drugs which ameliorated depression by changing the actions of various neurotransmitter systems in the brain. These early drugs, while very effective, not only blocked the uptake of serotonin into neurones, but also prevented the uptake of other neurotransmitters. Researchers felt that a drug which only affected the serotonergic system might be better at treating depression than these so called "dirty drugs" that caused massive changes in brain chemistry. They set out to synthesize a drug which would specifically block the uptake of serotonin without blocking the uptake of other neurotransmitters in the brain. Prozac is that drug, a selective serotonin reuptake inhibitor (SSRI). Prozac and other SSRI's act by blocking the uptake of serotonin at the presynaptic neurone. The resulting build-up of serotonin in the synapse causes the postsynaptic neurone to continue sending its message. This diagram shows the relative potencies of tricyclic antidepressants (desipramine, imipramine, nortriptyline and amitriptyline) and the SSRI fluoxetine in inhibiting NA and 5-HT reuptake.

The main effect of fluoxetine (Prozac) is to block the reuptake of serotonin into the presynaptic neurone. Amitriptyline does not exert a preferential effect on one neurotransmitter system. The other tricyclic antidepressants in this diagram have a greater effect on NA than 5-HT

It is thought that this excess of serotonin in the synapse and the concomitant increase in signal strength, intensity, and frequency of serotonin induced action potentials causes the elevation in mood clinicians see after patients begin taking Prozac. While this is not surprising, considering the role serotonin plays in the brain, there are a few problems with this theory. In vitro studies of Prozac indicate that it stops uptake of serotonin into neurones almost immediately but patients who take Prozac do not notice the salutary effects for an average of four weeks. This presents a problem because the in vivo results seem to indicate that there is something else (other than blocking the reuptake of serotonin) going on.

Here is a link to a very comprehensive article on the latest developments in serotonin research: Serotonin: The Neurotransmitter for the '90s by Ronald F. Borne, Department of Medicinal Chemistry, University of Mississippi.

In the light of the clinical success of Prozac several other SSRIs have been developed i.e. sertraline, paroxetine, fluvoxamine, and citalopram. Edwards and Anderson (1999) provide a comparative review of their efficacy and side effects ( Drugs 1999 Apr; 57(4): 507-33 )

Side Effects of Tricyclic Antidepressants and Prozac

Antidepressant drugs produce side effects. Older antidepressants (tricyclics) and Prozac differ in their side effect profile. It is up to you to decide if one side effect profile is more desirable than another.

Click on the blue underlined text to compare the adverse side effects produced by a modern specific serotonin reuptake inhibitor (SSRI) and older tricyclic antidepressants (TCA): Prozac (fluoxetine) (SSRI) amitriptyline (TCA) imipramine (TCA) placebo Compare all drugs It is clear that fewer patients taking the SSRI report adverse reactions, and that the majority of patients on the older drugs experience a dry mouth .

Antidepressants on the horizon. You may have formed the impression that contemporary drug development is tightly focussed on chemicals that block serotonin uptake. This is not strictly true. There is considerable interest in drugs that block the effects of different versions of the enzyme MAO ( m ono a mine o xidase) that breaks down monoamines. In addition, the development of drugs that selectively inhibit noradrenaline uptake may cause renewed interest in the role of NA in depression.

• inhibiting MAO-A increases norepinephrine, dopamine and serotonin in the synaptic cleft
• inhibiting MAO-B increases dopamine in the synaptic cleft
• reboxetine - the first selective noradrenaline reuptake inhibitor increases NA in the synaptic cleft

The Current Status of Antidepressant Drugs

Despite nearly 50 years of relatively effective biological treatments for depression we are still using drugs that share many of the limitations of classic antidepressant drug therapies.

Contemporary drugs suffer from:

• Therapeutic lag . It may take 1-4 weeks before antidepressant effects are fully developed. A number of explanations for this effect have been suggested.
  • Blood levels of antidepressants may not reach adequate concentrations on first administration. Studies have shown a positive correlation between plasma drug level and therapeutic response.
  • It is unrealistic to expect immediate improvement in patients who have had cognitive and emotional problems for some time before drug therapy commenced.
  • The behavioural scales used to measure improvement are subjective and may be insensitive to small improvements during the early stages of treatment.
• Adverse side effects . we have explored the type and frequency of adverse side effects produced by TCAs and SSRI drugs.
• Limited effectiveness (i.e. only 70+% of depressions respond to TCA or SSRIs)

In addition we have a limited understanding of the biological bases of depression(s). Our theoretical understanding is still rooted in the monoaminergic theory of depression . Existing animal models seem to be developed on the basis of sensitivity to existing drug types rather than a fundamental understand of the biological basis of depressed behaviour.

One possible new avenue for theoretical and practical advance is the notion that depression may involve a fundamental abnormality in the h ypothalamus- p ituitary- a drenal (HPA) system - the body's stress response system.

Role of the hypothalamus pituitary adrenal system in depression

The organization of the hypothalamus pituitary adrenal system is described in detail in a separate lecture in this series. Briefly: Stressful environmental stimuli trigger the release of corticotrophin releasing factor (CRF) from nerve cells in the the hypothalamus into a blood system that travels to the anterior pituitary. In response to CRF, the anterior pituitary releases adrenocorticotrophic hormone (ACTH) into the blood system. ACTH is transported to the remotely located adrenal gland. ACTH stimulates the production of cortisol in the adrenal cortex. Cortisol is released into the blood stream Cortisol is transported back to the brain where it reduces further ACTH release through a negative feedback system

"Hundreds, perhaps even thousands, of studies have confirmed that substantial numbers of depressed patients - particularly those most severely affected - display hypothalamus pituitary adrenal system hyperactivity. Indeed, the finding is surely the most replicated one in all of biological psychiatry." Nemeroff (1998). This figure shows data reported by Bunney et al (1969) who found very high cortisol levels in depressed patients who subsequently committed suicide. A very important question is whether increased HPA activity is a cause or correlate of depression. Does some product of the HPA (cortisol, ACTH or CRF) make people depressed, or is increased cortisol secretion simply a symptom correlated with depression? The first step to discovering answers to these questions involves investigating the reason for increased cortisol secretion in depression. Is it due to an abnormality in the adrenal cortex, pituitary gland or hypothalamus?

Cortisol is an essential component of the negative feedback system that controls ACTH secretion from the anterior pituitary. High levels of circulating cortisol feedback to the hypothalamus to reduce CRF and ACTH secretion. Cortisol levels may be high in depression because of a fault in the mechanisms that control the body's response to stress. This can be tested by using the potent synthetic steroid dexamethasone (DXM). In normal people DXM shuts down the pituitary adrenal system by mimicking the effect of cortisol. This effect can be seen by measuring the reduced level of cortisol in the person's blood stream after they have been given DXM. The next section describes the abnormal response to this dexamethasone suppression test in depression.

Depression is associated with increased activity in the hypothalamus-pituitary-adrenal (HPA) system which manifests itself as an increase in the level of cortisol in the blood stream of people suffering from depression. Dexamethasone (DXM) is a powerful synthetic steroid that activates the negative feedback loop in the hypothalamus pituitary adrenal system. Normal and depressed people given DXM show a profound reduction in their level of circulating cortisol. This effect is shown in the diagram. But, about 50% of depressed patients exhibit " escape " from DXM suppression. Note the increase in cortisol in depressed patients the day after DXM was taken. This finding led to the suggestion that there is some fundamental problem with the control of the HPA in depression. Recently hypotheses have focussed on the possibility of a link between abnormal HPA activity and disturbances in neurotransmitter systems that control the release of CRF.

It is important to point out that the role of neurotransmitters in controlling the HPA has been suspected for several years, but it is only relatively recently that attention has focussed on the possibility of developing treatments for depression based on the idea that abnormal HPA activity causes depression.

• Lopez et al (1997 ) hypothesize that the 5-HT (serotonin) receptor changes observed in suicide brains may be a result of, or may be worsened by, the HPA overactivity that may be present in some suicide victims.

They review the literature which suggests that:

1. chronic unpredictable stress produces high corticosteroid levels in rats;
2. chronic stress also results in changes in specific 5-HT receptors (increases in cortical 5-HT2A and decreases in hippocampal 5-HT1A and 5-HT1B);
3. chronic antidepressant administration prevents many of the 5-HT receptor changes observed after stress; and
4. chronic antidepressant administration reverses the overactivity of the HPA system.

If 5-HT receptors have a partial role in controlling affective states, then their modulation by cortisol provides a potential mechanism by which these hormones may regulate mood. These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance.

Nemeroff's Stress-Diathesis Model of Mood Disorders

Charles Nemeroff has developed a model of how early stressors such as child-abuse or neglect and genetic predisposition could account for depression in adulthood. [Nemeroff (1998); Arborelius et al,(1999)].

His model is based on the following well established findings in biological psychiatry:

• In depression both the adrenal gland and the pituitary are enlarged, and the adrenal gland hypersecretes cortisol.
• CRF ( c orticotrophin r eleasing f actor) concentrations in cerebrospinal fluid is elevated in depressed patients, compared with control subjects or individuals with other psychiatric disorders
• This magnification of CRF levels is reduced by treatment with antidepressants and by effective electroconvulsive therapy
• Postmortem brain tissue studies have revealed a marked exaggeration both in the number of CRF-producing neurons in the hypothalamus and in the expression of the CRF gene (resulting in elevated CRF synthesis) in depressed patients as compared with controls.
• Delivery of CRF to the brains of laboratory animals produces behavioral effects that are cardinal features of depression in humans, namely, insomnia, decreased appetite, decreased libido and anxiety.

Nemeroff uses this line of argument to develop his model:

• Depression runs in families. this means that certain genetic traits in the affected families somehow lower the threshold for depression
• Conceivably, the genetic features directly or indirectly diminish monoamine levels in synapses or increase reactivity of the HPA system to stress.
• The genetically determined threshold is not necessarily low enough to induce depression in the absence of serious stress but may then be pushed still lower by early, adverse life experiences.
• Early abuse or neglect not only activates the stress response but induces persistently increased activity in CRF-containing neurons, which are known to be stress responsive and to be overactive in depressed people.
• If the hyperactivity in the neurons of children persisted through adulthood, these supersensitive cells would react vigorously even to mild stressors.
• This effect in people already innately predisposed to depression could then produce both the neuroendocrine and behavioral responses characteristic of the disorder.

Nemeroff uses the following evidence to support his model:

• Neonatal rat pups were removed from their mothers for brief periods on about 10 of their first 21 days of life
• As adults, these maternally deprived rats showed clear signs of changes in CRF-containing neurons, all in the direction observed in depressed patients--such as rises in stress-induced ACTH secretion and elevations of CRF concentrations in several areas of the brain.
• Levels of corticosterone (the rat's cortisol) also rose
• CRF-receptor density was increased. Nemeroff points out that this is a strange result because receptor density usually increases to compensate for a reduction in a neurotramsmitter
• Demeroff argues that elevated receptor concentrations would tend to magnify the action of CRF, thereby enhancing the depression-inducing effects of CRF and stress. But he does not present evidence that CRF induces depression
• Treatment with the selective serotonin reuptake inhibitors returns CRF levels to normal
• How inhibition of serotonin reuptake would lead to normalization of the HPA system is unclear, but neurotransmitters may be involved in controlling CRF release

Apparently some pharmaceutical companies are developing CRF receptor blockers as potential antidepressant drugs.

 
Fawcett's Model of Suicide

Fawcett et al (1997) have proposed a four factor model of suicide risk that brings together the various biological factors we have explored in lectures:

1. severe anxiety/agitation associated with high brain corticotrophin-releasing factor (CRF) levels - indicates excessive hypothalamic-pituitary-adrenal activation
2. trait baseline and reactivity hopelessness - possible link here with learned helplessness
3. severe anhedonia - indicating abnormality in the brain reward/reinforcement system
4. trait impulsiveness associated with low brain serotonin turnover - this research was initiated by Asberg

References :

• Arborelius et al, (1999). Journal of Endocrinology , 160, 1-12.
• Asberg (1976). Science , 191, 478-480.
• Berman et al (1999). Arch Gen Psychiatry 56(5):395-40.
• Bunney et al (1969). Archives of General Psychiatry, 21.
• Csernansky & Posener (1999). Arch Gen Psychiatry , 56(5)
• Edwards and Anderson (1999). Drugs, 57(4): 507-33.
• Fawcett J, Busch KA, Jacobs D, Kravitz HM, Fogg, (1997). Ann N Y Acad Sci 836:288-301
• Feldman et al (1997). Principles of Neuropsychopharmacology , Sinauer, Massachusetts.
• Kohn, The Independent on Sunday , 9th January 2000, pp14-16
• Lopez et al (1997). Ann N Y Acad Sci, 836:106-34 )
• Schatzberg & Schildkraut (1995). In Psychopharmacology: The Fourth Generation of Progress (F.E. Bloom and D.J. Kupfer, Eds.), pp911-920, Raven Press, New York.
• Schildkraut (1965). American Journal of Psychiatry, 122, 509-522.

Online Resources  

• L Arborelius, M J Owens, P M Plotsky and C B Nemeroff (1999) The role of corticotropin-releasing factor (CRF) in depression and anxiety disorders. Journal of Endocrinology Volume 160, Issue 1
• Charlton, B. (2000). The malaise theory of depression: Major depressive disorder is sickness behavior and antidepressants are analgesic. Medical Hypotheses, 54: 126-130.
  Abstract: "It is proposed that major depressive disorder is inappropriate 'sickness behavior' generated by abnormalities in cytokines, and that antidepressants exert their specifically beneficial effects through analgesic action on the core dysphoric emotion of malaise. This is termed the malaise theory of depression, and leads to a wide range of testable predictions."
• Heim C . et al (2000). Pituitary-Adrenal and Autonomic Responses to Stress in Women After Sexual and Physical Abuse in Childhood Journal of the American Medical Association, Vol. 284.
  
  • From the abstract "Women with a history of childhood abuse exhibited increased pituitary-adrenal and autonomic responses to stress compared with controls. This effect was particularly robust in women with current symptoms of depression and anxiety. Women with a history of childhood abuse and a current major depression diagnosis exhibited a more than 6-fold greater ACTH response to stress than age-matched controls."
  • Press comment: E. Goode, "Childhood Abuse and Adult Stress" The New York Times, August 2, 2000
• Lott, 1999 Childhood Trauma, CRF Hypersecretion and Depression. Psychiatric Times October 1999 Vol. XVI Issue 10. Based on presentaion by Nemeroff, 1999 'The Persistent Neurobiological Consequences of Early Untoward Life Events: Treatment Implications'.
• Nemeroff (1998). 'The Neurobiology of Depression'. Scientific American ,June 1998
• U.S. Department of Health and Human Services . Mental Health: A Report of the Surgeon General (1999).
  Chapter 4: Adults and Mental Health Section Etiology of Mood Disorders