Depression monoamine theories

A logical conclusion from this work was that depression is caused by hyperresponsive )S-adrenoceptors. At first, this might seem to undermine Schildkraut s suggestion that depression is caused by a deficit in noradrenergic transmission. However, proliferation of receptors is the normal response to a deficit in transmitter release and so the opposite change, dowmegulation of jS-adrenoceptors by antidepressants, would follow an increase in the concentration of synaptic noradrenaline. This would be consistent with both their proposed mechanism of action and the monoamine theory for depression. 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

When Schildkraut introduced the monoamine theory of depression, he admitted that there was little direct evidence for it. Instead, it was based on the supposed effectiveness of antidepressant medication and the mistaken belief that reserpine makes people depressed. Schildkraut acknowledged that Most of this evidence is indirect, deriving from pharmacological studies with drugs such as reserpine, amphetamine and the monoamine oxidase inhibitor antidepressants which produce affective changes. 21 A half-century has passed since his chemical-imbalance theory of depression was introduced, and the presumed effectiveness of antidepressants remains the primary evidence in its support. But as we have seen, the therapeutic effects of antidepressants are largely due to the placebo effect, and this pretty much knocks the legs out from under the biochemical theory. 

During the last 50 years researchers have tried to find more direct evidence for the monoamine theory of depression, but by and large they have failed. Instead of finding confirmation, much of the evidence they have found is contradictory or runs counter to the... 

Although there has been a substantial body of pharmacological evidence in support of the monoamine theory of depression, clinical biochemical data have been less convincing (Luchins, 1976) this is where differences in the concentrations of NA and 5-HT and their metabolites or hormones, which are ultimately under the control of brain monoaminergic neurons (neuroendocrine markers), have been compared between depressed patients and normal controls. However, by the early 1970s a major difficulty with the theory was becoming apparent this was the time lag between the immediate... 

What is the evidence for the monoamine theory of depression, and which key observations led to its revision ... 

Heninger GR, Delgado PL, Charney DS. (1996). The revised monoamine theory of depression a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry. 29(1) 2-11. 

The second neurotransmitter implicated in the monoamine theory was 5-HT (13). Indeed, more than 30 years ago, Bunney and Davis (13) noted that 5-HT may also be a candidate neurotransmitter involved in depression. 

The monoamine theory of depression is important because it provides a model for the idea that antidepressant drugs act on the biological basis of depressive symptoms. It forms the basis for the modern idea that depression arises from a chemical imbalance. 

Despite decades of research, there is no evidence to support the monoamine theory of depression (see Chapter 9). Studies of noradrenalin are inconsistent, with as many finding raised levels in people with depression as those finding reduced levels (Dubovsky, Davies, Dubovsky 2002). Evidence on serotonin is similarly inconsistent, and eminent mainstream psychopharmacologists admit that there is no evidence of serotonin dysfunction in depression (Lacasse Leo 2005). Nevertheless, the monoamine hypothesis has survived and remains influential. Contradictory evidence has been overlooked or reframed as supportive. For example, Schildkraut reported research that clearly showed that imipramine decreased noradrenalin levels in the brain, but hypothesised that despite reduced concentrations, the activity of noradrenalin might nevertheless be increased (Schildkraut, Winokur, Applegate 1970). 

Early formulations of the monoamine theory of depression cited two strands of evidence. One was the effects of antidepressant drugs and the other was the effects of reserpine. Skildkraut believed that studies have shown a fairly consistent relationship between drug effects on catechloamines, especially norepinephrine, and affective or behavioural states (Schildkraut 1965, p. 509). He went on to describe how drugs that cause depletion and inactivation of norepinephrine centrally produce sedation or depression, while drugs which increase or potentiate brain norepinephrine are associated with behavioural stimulation or excitement and generally exert an antidepressant effect in man (p. 509). 

Several theories have attempted to explain the pathology of depression. One of these theories is the monoamine theory of depression (Heninger et al., 1996). This theory proposes that impaired monoaminergic function is the central basis behind depression. Serotonin and norepinephrine are the two monoamines that have been primarily implicated in the disease. Pharmacological treatment of depression has focused on increasing synaptic levels of these two neurotransmitters (Table 3). 

This data, coupled with numerous positive outcome studies of the effectiveness of antidepressants, has led to the development of the monoamine (or biogenic amine) hypothesis of depression. The theory holds that depressive symptoms are ushered in by a malfunction of either norepinephrine (NE) or serotonin (5-HT) neurons, which play critical roles in the functioning of the limbic system and the adjacent hypothalamus. The basic neuronal malfunction is felt to be identical for either NE or 5-HT neurons, thus what follows (a description of the pathophysiology of NE neurons) can also be seen to occur in individuals in whom 5-HT neurons are affected. For reasons that are not well understood, patients with major depression (with vegetative symptoms) appear to suffer from either NE or 5-HT dysfunction, but probably not both simultaneously (although some exceptions exist). 

Introduction - Concern over the safety of tricyclic antidepressants (TCA)f> has maintained the Impetus to develop new drugs. Compounds reviewed in 1978 Include mianserin,3. nomlfensin, and all non-TCA. S5rm-posia covered dothlepin, mianserin, nomifensin, and trazodone. The uses of L-tryptophan and 5-hydroxytryptophan (5-HTP) in depression and the properties of the new antidepressants " were summarized. The neuropharmacology of depression, and the mechanism of action and pharmacokinetics of antidepressants were reviewed, and the monoamine theory reassessed.20... 

Despite evidence for and against, there remains one major problem with the monoamine theory of depression. All antidepressants take weeks to have an effect, which is far longer than it takes to alter brain amines. It has been suggested that effects of antidepressants are due to adaptive changes in the brain, which may involve down regulation of receptors or some other change in their sensitivity. 

Briefly describe the monoamine theory of depression and mania. What is the major problem with this theory ... 

Tile cause of depression and the mechanism of aeiion of antidepressants are unknown. The monoamine theory wa.s ba.sed on the idea that depression resulted from a dcctea.se in the activity of central noradrenergic and/or serotonergic systems. There are problems with thi.s theory, but it has not been replaced with a heeler one. More recently, interest has focused on the mechanism of action of aniidepressanis. 

There was a problem with this first version of the biochemical theory of depression. Iproniazid was not the only drug that had been reported to be effective as an antidepressant. Imipramine, the drug that had been tested by the Swiss psychiatrist Roland Kuhn, seemed to have similar effects. But imipramine is not an MAOI it does not inhibit the destruction of neurotransmitters in the synapse. So if antidepressants worked by inhibiting monoamine oxidase, why was imipramine effective How could its apparent effectiveness be reconciled with the chemical-imbalance theory ... 

When the reserpine studies are added to the antidepressant studies, the logic behind the chemical-imbalance theory begins to look compelling. Drugs like reserpine that decrease monoamine neurotransmitters make people depressed. Drugs that increase these neurotransmitters by one means or another relieve their depression. Hence, depression is due to a monoamine deficiency. 

How is it that the chemical-imbalance theory was proposed and so widely accepted, when the only controlled scientific study that had been done indicated that one could relieve depression, rather than induce it, by giving patients a drug that increases brain levels of monoamines David Healy, in his comprehensive treatise on the history of antidepressants, provides an answer to this question.19 The study was simply ignored, despite having been published in The Lancet, one of the world s most prestigious medical journals. 

Neurochemical theories for the affective disorders propose that there is a link between dysfunctional monoaminergic synapses within the central nervous system (CNS) and mood problems. The original focus was the neurotransmitter noradrenaline, or NA (note noradrenaline is called norepinephrine, or NE, in American texts). Schildkraut (1965) suggested that depression was associated with an absolute or relative deficiency of NA, while mania was associated with a functional excess of NA. Subsequently, another monoamine neurotransmitter 5-hydroxytryptamine (5-HT), or serotonin, was put forward in a rival indoleamine theory (Chapter 2). However, it was soon recognised that both proposals could be reconciled with the available clinical biochemical and pharmacological evidence (Luchins, 1976 Green and Costain, 1979). 

As with the dopamine theory of schizophrenia, the monoamine hypotheses of depression emphasize one or more aspects of the actions of clinically effective... 

In the mid-1960 s, Schiidkraut and Bunney and Davis, independently developed the monoamine hypothesis of mood disorders. To date, a great wealth of data has been generated to test this theory (see also the section Mechanism of Action in Chapter 7) (21, 22). Because the early development of psychotropic agents was based on the concept that altering norepinephrine (NE) or serotonin activity could benefit depression or mania, it is not surprising that the action of these drugs... 

Strong support for the biogenic amine theory of depression is provided by the powerful antidepressant effect of inhibitors of monoamine oxidase. An example is pargyline (Fig. 30-33), which forms a covalent... 

The first major theory about the biological etiology of depression hypothesized that depression was due to a deficiency of monoamine neurotransmitters, notably norepinephrine (NE) and serotonin (5-hydroxytryptamine [5HT]) (Figs. 5 — 13 through... 

FIGURE 5—60. The monoamine receptor hypothesis of depression posits that something is wrong with the receptors for the key monoamine neurotransmitters. Thus, according to this theory, an abnormality in the receptors for monoamine neurotransmitters leads to depression. Such a disturbance in neurotransmitter receptors may be caused by depletion of monoamine neurotransmitters, by abnormalities in the receptors themselves, or by some problem with signal transduction of the neurotransmitter s message from the receptor to other downstream events. Depicted here is the normal monoamine neuron with the normal amount of monoamine neurottansmitter and the normal amount of correctly functioning monoamine receptors. 

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