the monamine hypothesis of depression states that

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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Monoamine hypotheses of mood disorders.

Jack D Barchas and Margaret Altemus .

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• Biogenic amines have been important in hypotheses of mood disorders

The catecholamine hypothesis of depression was an important organizing step that helped to define modern biological research in psychiatry [ 22 – 24 ]. It states that depression is caused by a functional deficiency of catecholamines, particularly norepinephrine ( NE ), whereas mania is caused by a functional excess of catecholamines at critical synapses in the brain. This hypothesis was based on a correlation of the psychological and cellular actions of a variety of psychotropic agents. Other biogenic amines in the brain have also been linked to depression and mania with the development of monoamine or biogenic amine hypotheses. These amines have included the indolamine serotonin (5-hydroxytryptamine [ 5-HT ]) and two catecholamines in addition to NE , dopamine ( DA ) and epinephrine.

• A number of strategies are used to investigate neuroregulators in mood disorders

Several strategies have been used to examine the role of monoamines in the mood disorders. Precursor loading entails administering precursors of biogenic amines to subjects to raise monoamine concentrations in the brain. The serotonin precursors l -tryptophan and 5-hydroxytryptophan ( 5-HTP ), with or without concomitant antidepressant medication, and the catecholamine precursors tyrosine and levodopa have been attempted as therapeutic regimens. None of these compounds is in routine clinical use for mood disorders. Blockers of neurotransmitter degradation, such as monoamine oxidase ( MAO ) inhibitors, have also been employed, as described below. See Chapters 12 and 13 regarding the metabolism and synaptic effects of these amines.

Another approach has been to deplete amines by dietary means or by administering inhibitors of enzymes involved in the formation of biogenic amines. Although dietary depletion of tryptophan, the serotonin precursor amino acid, does not change mood in unmedicated depressed subjects, this procedure produces a relapse of depression in recovered subjects who have been treated with antidepressant medication or light therapy. Dietary tryptophan depletion also can induce depressive symptoms in subjects with a family history of depression but not in control subjects. Similarly, para-chlorophenylalanine ( PCPA ), an inhibitor of tryptophan hydroxylase, lowers levels of 5-HT and has been found to reverse the antidepressant effects of imipramine but to have no effect on mania. A competitive inhibitor of tyrosine hydroxylase, α-methyl-para-tyrosine ( AMPT ), which lowers levels of catecholamines, also has been reported to worsen depression in some previously depressed patients treated with antidepressant medication. In addition, AMPT appears to improve mania in some patients. These intriguing findings are the subject of ongoing research.

Another important strategy has involved studies of the metabolites of the neuroregulators by determination of their concentrations in cerebrospinal fluid ( CSF ), blood or urine. There has generally been considerable inconsistency in such studies, but this may reflect not only the fact that such methods involve a summation of many events in many areas of the brain but also that the bulk of monoamine transmitters released at synapses does not spill over into the CSF or peripheral circulation. Techniques have been developed, based on radiolabeled tracers, to more accurately estimate synaptic spillover of catecholamines under different conditions. These studies have shown enhanced plasma noradrenergic activity in patients with severe agitated depression. Additional difficulties arise from the necessarily small number of subjects in these sampling studies and the likelihood of substantial clinical heterogeneity with possibly multiple disorders presenting as common syndromes.

• Catecholamine hypotheses remain important for depression and mania

The norepinephrine-deficiency hypothesis of depression had several roots: one observation concerned the natural alkaloid reserpine. Treatments involving reserpine had been used in India for centuries as a treatment for mental illness. Beginning in the 1950s, reserpine was used more widely for the treatment of hypertension and schizophrenia. It was noted that, in some patients, reserpine caused a syndrome resembling depression. Animals given reserpine also developed a depression-like syndrome, consisting of sedation and motor retardation. Subsequently, it was demonstrated that reserpine caused the depletion of presynaptic stores of NE , 5-HT and DA . While it is now recognized that depression is relatively uncommon following reserpine administration, the drug had a key role in the development of psychopharmacology and was a powerful impetus to the study of the biochemistry of neuroregulators in the brain.

In contrast to reserpine, iproniazid, a compound synthesized in the 1950s for the treatment of tuberculosis, was reported to produce euphoria and hyperactive behavior in some patients. It was found to increase brain concentrations of NE and 5-HT by inhibiting the metabolic enzyme MAO . Iproniazid as well as other MAO inhibitors were soon shown to be effective in alleviating depression.

The clinical and cellular actions of tricyclic antidepressants, such as amitriptyline, were considered to support the monoamine hypothesis of mood disorders. These drugs, resulting from a modification of the phenothiazine nucleus, were found to alleviate depression consistently, as did the MAO inhibitors. Their major cellular action is to block the reuptake by presynaptic terminals of monoamine transmitters, thereby, presumably, increasing the concentration of monoamines available to interact with synaptic receptors. Thus, the actions of reserpine, MAO inhibitors and tricyclics were initially thought to be consistent in supporting the monoamine hypothesis.

Inconsistencies arose, however. The pharmacological activities of several other clinically effective compounds are difficult to reconcile with the monoamine hypothesis. Several antidepressant agents do not significantly inhibit MAO or block the reuptake of monoamines. The antimanic agent lithium (discussed below) can also be used to treat depression, yet it does not chronically increase synaptic concentrations of monoamines. Conversely, cocaine, a potent inhibitor of monoamine reuptake, has no antidepressant activity.

More detailed examination of the actions of reserpine, MAO inhibitors and tricyclics also reveals inconsistencies among their actions. Reserpine induces depression in only about 6% of patients, an incidence quite similar to the estimated incidence of depression in the general population. More importantly, the cellular effects of MAO inhibitors and tricyclic antidepressants on catecholamines are immediate, yet their clinical antidepressant effects develop quite slowly, generally over 2 to 6 weeks.

Attempts to directly measure changes in brain monoamine concentrations in the mood disorders have provided intriguing but inconsistent results. Initially, investigators concentrated on measuring the catecholamine metabolite 3-methoxy-4-hydroxyphenylglycol ( MHPG ), in urine and CSF . Early evidence suggested that there were decreased urinary MHPG concentrations in depressed patients and increased levels in manic patients but later reports did not bear this out. This is not entirely surprising as it is now known that urinary MHPG is a poor indicator of CNS NE turnover because the CNS contributes as little as 20% of urinary MHPG content. In addition, MHPG concentrations are substantially affected by physical activity, which was often not well controlled in research studies. Concentrations of MHPG in the CSF, which may represent a more direct measure of brain NE function, have generally been found to be unaltered in mood disorders, although this remains a controversial area (see Chap. 12).

• Dopamine mechanisms may be important in some forms of depression and mania

DA may also be involved in depression, and a body of literature suggests that there may be a subgroup of mood disorders in which the neuroregulator is altered [ 18 – 21 ]. DA receptor agonists have been reported to have some antidepressant effects in at least subgroups of patients. A number of antidepressant drugs also have DA agonist activities. Furthermore, patients in the DA-depleted state of Parkinson's disease (see Chap. 45) often develop a concomitant depression, although that may be for other reasons. Conversely, there is evidence linking DA to mania in certain patients. Several drugs that increase available amounts of DA produce behaviors that simulate some aspects of mania. Administration of levodopa ( l -DOPA), the metabolic precursor of DA, can induce hypomania in some patients, a finding particularly noted in persons with bipolar disorder. In addition, DA antagonists are useful pharmacological treatments for mania, and there is evidence that DA synthesis inhibitors may also be effective. Neuroleptic drugs are also important agents for resolution of psychotic symptoms that occur in severe cases of both mania and depression [ 18 ]. However, there are problems with postulating a primary role for DA in the mood disorders. Most notably, neuroleptic medications that are known to block DA receptors and used to treat psychosis (Chap. 51) are not generally associated with the induction of depression. It is more likely that other, primary pathophysiological processes impact on dopaminergic systems, especially in more severe, psychotic forms of affective illness.

Studies of the major metabolite of DA in CSF , homovanillic acid ( HVA ), have been somewhat inconsistent, suggesting decreased concentrations in at least some patients with depression. Comparison between studies has been difficult due to small sample size and differences among clinical populations, including age differences. A number of studies have suggested elevated concentrations of the metabolite in the CSF of manic individuals. However, metabolites for other transmitters were also elevated in some of these studies.

• Serotonin has a role in some forms of depression

A major hypothesis is that some forms of mood disorder may be due to a relative deficiency of serotonin [ 18 – 21 , 25 ]. The efficacy of several new antidepressant medications that have a high specificity as serotonin-reuptake blockers has been taken as a form of proof of the existence of such a subtype of patients. Preclinical studies indicate that chronic administration of these drugs increases the efficiency of serotonergic neurotransmission. Further support for this hypothesis comes from repeated findings of precipitation of depression during serotonin depletion in vulnerable individuals, as described above. In addition, cerebral metabolic responses to the 5-HT -releasing agent fenfluramine (see Chap. 13) are reduced in patients with depression.

One of the most consistent findings in biological research dealing with mental disorders has been that some patients with low CSF 5-hydroxyindoleacetic acid ( 5-HIAA ) are prone to commit suicide [ 26 ]. The lower concentrations of 5-HIAA are not specific to depression; there has also been a correlation between decreased 5-HIAA and aggressive behavior in some individuals.

• Cite this Page Barchas JD, Altemus M. Monoamine Hypotheses of Mood Disorders. In: Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.
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Neurobiology of Depression

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Hypotheses about the pathophysiology of depression have evolved over time. This chapter covers the most important findings in this regard. First, the classical monoamine hypothesis posited that depression is caused by an alteration in levels of one or more of the monoamines: serotonin, norepinephrine, and dopamine. More recently, research on the glutamatergic system has aroused great interest by examining the mechanism of action of ketamine, an N-methyl-D-aspartic acid (NMDA) receptor antagonist. Likewise, stressful life events can precipitate depressive episodes in vulnerable individuals. Abnormalities in the HPA axis have been associated with a hyperactive response to stress in depressed patients (the diathesis-stress model). Increased levels of inflammatory markers have been found in patients with depression and anti-inflammatory agents are being studied as antidepressants. Reduced production of BDNF and neuroplasticity can lead to depression. These pathophysiological mechanisms are reciprocally connected with each other. Major Depression is a heterogeneous entity and a variety of biological mechanisms may be involved.

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Silva, H. (2021). Neurobiology of Depression. In: Jiménez, J.P., Botto, A., Fonagy, P. (eds) Etiopathogenic Theories and Models in Depression. Depression and Personality. Springer, Cham. https://doi.org/10.1007/978-3-030-77329-8_8

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Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications

• Alexandria N. Tartt 1 ,
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Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift toward a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural, and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.

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• Alexandria N. Tartt

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Conception: AT and MB. Original draft—AT, MM, and MB. Clinical insights—JJM and MB. Editing: JJM and RH. All authors revised the literature, reviewed, edited, and approved the final version.

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Tartt, A.N., Mariani, M.B., Hen, R. et al. Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications. Mol Psychiatry 27 , 2689–2699 (2022). https://doi.org/10.1038/s41380-022-01520-y

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DOI : https://doi.org/10.1038/s41380-022-01520-y

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4.1  The monoamine hypothesis of mood disorders

In the 1950s it was noticed that around 20% of those patients prescribed the drug reserpine, used at the time to control high blood pressure, developed severe depression as a side effect.

It was subsequently discovered that reserpine depletes a group of neurotransmitters called monoamines, which include serotonin, noradrenalin and dopamine. Recall from earlier in this course that neurotransmitters are chemicals that neurons use to communicate with one another. Once neurotransmitter is released into a gap between neurons it must effectively bind to (join on to) an adjacent neuron in order to pass on its message. The point where it binds is known as a ‘receptor’. Every neuron therefore has a multitude of receptors for receiving neurotransmitter molecules. These receptors are like the glucocorticoid receptors that you saw in Activity 6.

Reserpine actually works inside neurons by preventing monoamines from being taken up into vesicles, leaving them vulnerable to being broken down inside neurons. Vesicles are small ‘bubbles’ inside neurons in which neurotransmitters are stored after they are made by the neuron and before they are released into synaptic gaps, the gaps between neurons – see Figure 9.)

What are the consequences if reserpine stops monoamine neurotransmitter from entering its vesicles?

There will be less of it available for release into the synaptic gap. So communication between neurons using this neurotransmitter will be hampered – cells are not able to signal to one another using this particular signal as effectively.

Around the same time it was noticed that tuberculosis patients, prescribed a different drug, i soniazid, sometimes experienced a lifting of pre-existing depression. Isoniazid inhibits (slows down or prevents the activity of) the substance monoamine oxidase (MAO). MAO is important because it breaks down monoamine neurotransmitters. As MAO destroys monoamines, inhibiting MAO would have the net effect of increasing the levels of monoamines available for neuron to neuron communication.

Such monoamine oxidase inhibitors (or MAOIs) became the first generation of antidepressants.

Subsequently it emerged that there was yet another way that available monoamine levels might increase: imipramine, another antidepressant, inhibited the reuptake of serotonin and noradrenalin that had been released into the synaptic gap (Figure 9). Reuptake is a clever process by which neurons try to reuse the neurotransmitter they have released. They simply take it back into themselves via special reuptake channels and try to package it neatly back into the vesicles (or storage bubbles) ready to be released the next time the neuron needs to signal to another neuron.

The diagram shows secretion, receptor binding and reuptake of serotonin. The serotonin is contained inside a vesicle in the presynaptic neuron, the vesicle moves to the cell membrane and discharges the serotonin into the synaptic gap. Serotonin then binds to its receptors on the postsynaptic neuron. Finally the serotonin is taken back into the presynaptic neuron by the serotonin reuptake transporter.

What effect would inhibition of reuptake have on neurotransmission involving monoamines such as serotonin and noradrenalin?

It would increase the amount of monoamines in the synaptic gap, so it would enhance neurotransmission as more would be available to bind to receptors enabling the process of neuron to neuron communication.

These findings about monoamines caused much excitement and led to the monoamine hypothesis of mood disorders. This postulated that monoamine levels have a primary role in causing depression, as lowering the levels of monoamines causes depression, while raising them lifts depression (see Hirschfeld (2000) for an overview). The mechanism postulated for this is shown in Figure 10.

All three parts of the figure show events at a monoamine synapse. In (a) the monoamine is contained in vesicles in the neuron, it emerges into the synaptic gap as the vesicles merge with the cell membrane, it binds to a proportion of the receptors on the neighbouring neuron, and move back into the original neuron through the reuptake channels, completing the cycle. In (b) there are fewer vesicles so less transmitter is released, resulting in reduced occupancy of the receptors. In (c) the reuptake channels are blocked by a reuptake inhibitor, so there is more monoamine bound to receptors on the neighbouring neuron.

ADMs that inhibit the reuptake of specific monoamines such as serotonin (SSRIs, selective serotonin reuptake inhibitors), noradrenalin (noradrenergic reuptake inhibitors, NRIs), or combinations of monoamines such as serotonin and noradrenalin (serotonin noradrenergic reuptake inhibitors, SNRIs) are nowadays amongst the most prescribed drugs in Western societies, showing that the biomedical approach, and the monoamine hypothesis, still have a powerful influence on the treatment of depression. This is, in part at least, because many people see drugs as a ‘quick fix’ for depression and there is pressure to prescribe them.

Activity 7 Neurotransmitters and mood disorders

Name the main neurotransmitters implicated in the monoamine hypothesis of mood disorders. Are the levels of these neurotransmitters higher or lower in people who are depressed?

Serotonin and noradrenalin. Their levels are lower in those who are depressed.

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PATHOPHYSIOLOGY AND CLINICAL PRESENTATION – CORRECT DIAGNOSIS

While the pathophysiology of depression is multifactorial and sometimes not well understood, the major framework for which we understand depression today is the monoamine hypothesis of depression. The monoamine hypothesis of depression states that depression is caused by a lowered amount of monoamines (norepinephrine, serotonin, and dopamine) in certain areas of the brain. Monoamines impact mood, attention, reward processing, sleep, appetite, and cognition so it is understandable that a functional deficit of monoamines in the brain could lead to depression (Brigitta, 2002). Levels of monoamine metabolites are markedly reduced in the cerebrospinal fluid of people with depression (McCance & Huether, 2014).

Regarding stress-induced depression, depression-like behavior has been shown in animal models to be linked with an atrophy of neurons in the hippocampus, a reduction in neurogenesis, and a deficit in hippocampal brain-derived neurotrophic factor (BDNF) levels (McCance & Huether, 2014). Researchers suggest that this deficit in BDNF, along with a reduction in neurogenesis, actually leads to a reduction in levels of monoamines in the brain which triggers depression.

Watch a short clip on the pathophysiology of major depression below : 

Video retrieved from: https://www.youtube.com/watch?v=KispXWwDaOc

In addition, literature has shown that depression is associated with the dysregulation of the Hypothalamus-Pituitary-Adrenal (HPA) Axis. When a stressor activates the HPA Axis it causes the release of cortisol.  Cortisol regulates many functions including metabolism, immune responses, and memory retrieval,  so it is understandable that dysregulation can lead to clinical manifestations of depression ( de Quervain  et al., 1998). When the HPA Axis is uncontrolled and chronically stimulated, cortisol and other glucocorticoids levels are elevated.  In fact, 30-70% of people with major depression have elevated cortisol levels contributing to depression and relapse.  These elevated cortisol levels can trigger an immune response to release inflammatory cytokines (interleukin 1α, IL-β, TNF and IL-6).  This inflammatory process sends signals throughout the body that stimulates the secretion of more hormones causing the HPA Axis to become hyperactive, metabolizing monoamines, which ultimately decreases serotonin synthesis (McCance & Huether, 2014).

HPA Axis Pathway

Picture Retrieved from:   http://adrenalfatiguesolution.com/wp-content/uploads/2013/10/HPA-diagram-horizontal.0021.jpg

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Revisiting the theoretical and methodological foundations of depression measurement

Affiliations.

• 1 Department of Clinical Psychology, Leiden University, Leiden, The Netherlands.
• 2 Department of Psychology, McGill University, Montreal, Quebec, Canada.
• 3 Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, US.
• 4 Department of Applied Psychology, Northeastern University, Boston, Massachusetts, US.
• PMID: 38107751
• PMCID: PMC10723193
• DOI: 10.1038/s44159-022-00050-2

Depressive disorders are among the leading causes of global disease burden, but there has been limited progress in understanding the causes and treatments for these disorders. In this Perspective, we suggest that such progress crucially depends on our ability to measure depression. We review the many problems with depression measurement, including limited evidence of validity and reliability. These issues raise grave concerns about common uses of depression measures, such as diagnosis or tracking treatment progress. We argue that shortcomings arise because depression measurement rests on shaky methodological and theoretical foundations. Moving forward, we need to break with the field's tradition that has, for decades, divorced theories about depression from how we measure it. Instead, we suggest that epistemic iteration, an iterative exchange between theory and measurement, provides a crucial avenue for depression measurement to progress.

Grants and funding

• K23 MH113805/MH/NIMH NIH HHS/United States