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The monoamine hypothesis

Dr. Simon Moss


According to the monoamine hypothesis, depression can be ascribed to deficits in the monoamine neurotransmitters: serotonin, dopamine, and noradrenaline (Coppen, 1967). The evidence of this hypothesis has primarily emerged from the apparent success of drugs that increase the concentration of these neurotransmitters, especially serotonin, in the synaptic clefts throughout the brain. Yet, despite the popularity of this hypothesis, many findings and observations challenge the legitimacy of this theory. For example, agents that deplete these monoamines, such as serotonin, noradrenaline, and dopamine, do not impair the mood of people who are otherwise healthy--although such agents do impair the mood of people whose clinical depression is in remission (Ruhe et al., 2007).

Drugs that affect the concentrations of serotonin, dopamine, or noradrenaline

Monoamine oxidase inhibitors

Monoamine oxidase inhibitors have been shown to diminish depression in certain circumstances. To clarify the role of monoamine oxidase inhibitors, a class of substances called monoamine oxidase reduces monoamines, such as serotonin, into its components. Therefore, monoamine oxidase diminishes the concentration of monoamines.

A variety of substances, such as ipronizid, mianserin, trazodone, and hyperforin, the active ingredient in St John's Wart, inhibit the functions of monoamine oxidase. These substances, collectively called monoamine oxidase inhibitors, therefore increase the concentration of monoamines, especially serotonin.

Consistent with the monoamine hypothesis, these monoamine oxidase inhibitors not only increase the concentration of monoamines but also have been shown to curb depression. For example, monoamine oxidase inhibitors have been shown to improve mood and increase activity in people who are not depressed (Rang et al., 2007). To illustrate, iproniazid nullified the psychotic depression that a drug used to treat high blood pressure can evoke (Potter et al., 2006). These observations imply that monoamines could diminish depression.

Yet, not only do these drugs generate side effects, monoamine oxidase inhibitors are not effective immediately. They tend to be effective only after several weeks, despite the more immediate increase in serotonin, challenging the monoamine hypothesis.

Tricyclic and tetracyclic antidepressants (TCAs)

Tricyclic and tetracyclic antidepressants comprise a series of drugs that impede the capacity of specific proteins, called transporter proteins, to transfer serotonin and noradrenaline from the synaptic cleft into the presynaptic cells. These drugs, therefore, diminish the concentration of serotonin and noradrenaline in the synaptic cleft.

Tricyclic and tetracyclic antidepressants comprise three or four contiguous rings respectively. These drugs include imipramine, desipramine, amitriptyline, and doxepin. Initially, these drugs can generate many side effects, such as sedation and confusion. These drugs have been shown to curb the symptoms of depression, at least after a few weeks. In particular, the increase of serotonin in the cleft is assumed to enhance mood and the increase of noradrenaline in the cleft is assumed to reduce somatic symptoms.

Selective reuptake inhibitors

In contrast to tricyclic and tetracyclic antidepressants that impede the reuptake of both serotonin and noradrenaline as well as sometimes dopamine, other drugs impede the reuptake of either serotonin or noradrenaline. Drugs that impede the reuptake of only serotonin are called selective serotonin reuptake inhibitors. Drugs that impede the reuptake of only noradrenalin are called selective noradrenalin reuptake inhibitors. Because of their selectivity, these drugs tends to generate fewer side effects but are as effective as tricyclic and tetracyclic antidepressants, at least for people with moderate rather than severe depression.

Evidence of whether drugs that increase concentrations of serotonin or noradrenaline are effective

Benefits of antidepressants

A multitude of studies has shown that antidepressants--specifically drugs that increase the concentration of monoamines--are more effective than placebos. These drugs tend to reduce depression, at least in particular circumstances.

Specifically, according to Wichers et al., (2008), antidepressants reduce the sensitivity of people to stress and, at least in some circumstances, increase their sensitivity to rewards. Perhaps related to this finding, serotonin and noradrenaline reuptake inhibitors increase the speed of emotional processing.

Limitations of antidepressants

Some researchers have revealed that often the benefits of antidepressants over placebos are limited in magnitude (Kirsch et al., 2002& Moncrieff et al., 2010). For example, in almost 60% of studies, over 80% of the individuals did not respond to the antidepressants (Kirsch et al., 2002). In addition, many studies that failed to support the efficacy of antidepressants have not been published (Pigott et al., 2010). The effects that are observed tend to manifest after several weeks, even though changes in monoamines are almost immediate, again challenging the notion that monoamines directly affect mood.

According to Fournier et al. (2010), antidepressants seem to be relatively ineffective in people with mild, moderate, or even severe levels of depression, as gauged by the Hamilton Depression Rating Scale. Yet, antidepressants have been shown to be more effective in people with very severe depression. Because Fournier et al. (2010) examined only the studies that fulfill strict criteria, such as studies in which the participants exhibited a broad range of depression levels and were outpatients, many other studies were excluded. Whether the conclusions would apply in these other circumstances remains to be assessed definitively.

Oken (2008), however, proposed that perhaps the limited efficacy of monoamines does not challenge the monoamine hypothesis. Some evidence indicates that placebos may also affect he concentration or efficacy of these neurotransmitters. Therefore, perhaps both the antidepressants and placebos increase the concentration and operations of monoamines and improve mood.

Cytokines, monoamines, and depression

The word cytokines is often used to describe substances that modulate the immune system, including the interleukins, interferons, colony stimulating factors, and tumor necrosis factors. Interleukins are often released by white blood cells or leukocytes and affect the development and differentiation of other white blood cells, including T cells, B cells, and hematopoietic cells. Interferons are released by infected cells and are proteins that impede viral replication and activate other immune cells, such as natural killer cells and macrophages.

The effects of cytokines are relevant to the monoamine hypothesis. Broadly, some of the cytokines that escalate the immune response--such as interleukin 1, interleukin 6, and tumor necrosis factors--tend to increase depression. Furthermore, according to Dantzer et al. (2007), similar cytokines diminish levels of tryptophan, a precursor of serotonin. Therefore, consistent with the monoamine hypothesis, bodily changes that curb serotonin also promote depression.

Other explanations for the relationship between cytokines and depression

Yet, researchers also highlight the relationship between cytokines and depression is complex. According to Glassman and Miller (2007), the association between cytokines, such as interleukin 1, interleukin 6, and tumor necrosis factors, and depression is not universal: Only a subset of depressed individuals exhibits these manifestations of inflammation.

Furthermore, the relationship between cytokines and depression may not be mediated by decreases in monoamines. For example, according to Raison et al. (2006), both cytokines and depression could be ascribed to an increase in stress and corticotropin releasing hormone or cortisol.

To clarify, stress tends to elicit two sequences of chemical changes. First, within seconds, stress increases activity of the sympathetic nervous system via the central nervous system. The sympathetic nervous system not only dilates pupils, increases the heart rate, constricts blood vessels, and inhibits digestion, but also activates the adrenal medulla, part of the adrenal gland, just above the kidneys, increasing the release of adrenaline into the blood.

Second, within minutes or hours, stress also increases the tendency of the hypothalamus in the brain to produce corticotropin releasing hormone. Corticotropin releasing hormone is sent to the pituitary gland, just under the hypothalamus, stimulating the release of a precursor to adrenocorticotropic hormone. Adrenocorticotropic hormone then travels to the adrenal cortex, part of the adrenal gland, increasing the release of cortisol--a chemical that generates many stress responses. Ultimately, cortisol diminishes the release of more corticotropin releasing hormone from the hypothalamus.

Importantly, the experience of stress, and the release of corticotropin releasing hormone and cortisol, could explain the association between cytokines and depression. That is, when stress is elevated, corticotropin releasing hormone increases the production of interleukin 1, interleukin 6, tumor necrosis factors, and other cytokines. In addition, when stress is elevated, cortisol can evoke a range of reactions that may provoke depression. These accounts imply the association between cytokines and depression may not be underpinned by a decrease in monoamines.

Evidence that may challenge the monoamine hypothesis

The 5-HTTLPR polymorphism of the SCL6A4 gene: Relationship with depression

5-HTTLPR is a region of the SCL6A4 gene. One variant of this region, called the short allele, has been shown to increase the level of serotonin in the synaptic cleft but increase the likelihood of depression, refuting the monoamine hypothesis.

To clarify, two meta-analyses, conducted by Lopez-Leon et al (2005) and Lopez-Leon et al (2008), identified which polymorphisms, or variants, of genes have been shown to be statistically related to depression. These meta-analyses were primarily confined to genes that have been examined in three or more studies. Taken together, polymorphisms of six genes were shown to be associated with major depressive disorder: DRD4, APOE e2, GNB3, MTHFR, SCL6A3, and SCL6A4. The gene that had been studied most often was SCL6A4.

This gene affects the concentrations of serotonin in the synaptic cleft. Specifically, this gene encodes or generates 5-HTT--a protein that transports serotonin away from the synapse after a nerve impulse.

This gene often, but not always, entails a region called the 5-HTTLPR--a region that influences the capacity of this gene to generate 5-HTT. Two variants of this 5-HTTLPR region have been differentiated: the short form and the long form, sometimes called the short allele or the long allele. The short form comprises 44 fewer pairs or components of DNA than does the long form.

For some people, both of the SCL6A4 genes comprise the short allele of this 5-HTTLPR region. For some people, both of the SCL6A4 genes comprise the long allele of this 5-HTTLPR region. For some people, one of the SCL6A4 genes comprises the short allele and the other SCL6A4 gene comprises the long allele. Yet, other combinations are possible. For example, in some people, only one of the SCL6A4 genes comprises this 5-HTTLPR region--and this region could be short or long. Relative to the long allele, the short allele diminishes the production of 5-HTT and, therefore, increasing the level of serotonin in the synaptic cleft.

Some research has shown the short allele of the 5-HTTLPR region is especially likely to coincide with indices or signs of depression, such as elevated amygdala activity (Dannlowski et al., 2007). These findings diverge from the predictions of the monoamine hypothesis. Admittedly, other research has shown this region is unrelated to depression.

The 5-HTTLPR polymorphism of the SCL6A4 gene: Moderating effects of the environment

During the 2000s, another hypothesis began to surface. Researchers showed the 5-HTTLPR polymorphism, especially the short allele, may be associated with depression only when people are exposed to very stressful environments (e.g., Caspi et al., 2003). Indeed, the 5-HTTLPR polymorphism may be associated with positive mood if people are exposed to supportive environments. Taken together, these observations indicate that, perhaps, the 5-HTTLPR polymorphism with the short allele is associated with sensitivity to the environment instead of depression (see Uher, 2008).

Related topics

Differential susceptibility perspective

The finding that depression is often associated with the short allele of the 5-HTTLPR polymorphism has, sometimes, been touted as evidence against the monoamine hypothesis. This short allele tends to increase levels of serotonin in the synaptic cleft but also augments the likelihood of depression (Andrews & Thompson, 2009). Yet, more recent evidence indicates this polymorphism, and perhaps other variants of genes as well, do not increase depression but merely augment the sensitivity of people to the environment (Uher, 2008). These people, therefore, are more likely to thrive in supportive conditions but struggle in unsupportive conditions

This possibility, called the differential susceptibility perspective, has received support outside the domain of depression. For example, some genetic variations are associated with low levels of aggression in supportive conditions but elevated levels of aggression in unsupportive conditions (e.g., Simons, Lei, Beach, Brody, Philibert, & Gibbons, 2012).

Specifically, Simons, Lei, Beach, Brody, Philibert, & Gibbons (2012) examined two genes or regions: the 5-HTTLPR region and the DRD4 gene. In both instances, a short or long allele have been distinguished. Unlike the 5-HTTLPR region, which affects the transportation of serotonin, the DRD4 affects the sensitivity of a dopamine receptor. For the DRD4 gene, the long allele codes less effectively than does the short allele.

Simons, Lei, Beach, Brody, Philibert, & Gibbons (2012) examined whether these polymorphisms are associated with aggression. The participants were teenagers and young adults, examined five times across 10 or so years. Participants reported whether they had engaged in aggressive behavior in the past year, including cruelty to animals, damaging property, fighting with weapons, and hurting another person. Next, four measures were administered to assess the extent to which the environment is supportive: the warmth and support of parents, positive attitudes to the school and teachers, participation in a religious community, and vigilant neighbors who, for example, punish vandalism. In addition, four measures were administered to assess unsupportive environments, such as harsh or abusive parenting, racial discrimination, target of crime or victimization, and violence of peers. Finally, some measures gauged hostility and chronic anger.

Overall, the results support the differential susceptibility perspective. In adverse environments, individuals with the short allele of the 5-HTTLPR region or the long allele of the DRD4 gene exhibited more hostility, anger, and ultimately aggression than other participants. Yet, in supportive environments, individuals with these polymorphisms exhibited less hostility, anger, and ultimately aggression than other participants. The behavior of people with these variants, therefore, seems to be more dependent on the social environment.

Side effects of antidepressants: Sexual dysfunction

The incidence of sexual dysfunction as a consequence of selective serotonin reuptake inhibitors is about 30 to 70%, including diminished sexual desire and difficulty achieving orgasm (for a review, see Safarinejad, 2010). This dysfunction is not only distressing but tends to curb compliance with the drug regime. These problems may be ascribed to the possibility that increases in serotonin activity on the Type 2 and 3 receptors impedes dopaminergic activity. Alternatively, these drugs may inhibit alpha-adrenergic and cholinergic receptors in the genito-urinary tract or increase the production of nitric oxide.

Safarinejad (2010) showed that bupropion may reverse these problems. In this study, 218 women were randomly assigned to receive 12 weeks of treatment with either bupropion sustained release or a placebo. The women completed measures of female sexual function and treatment satisfaction. Bupropion significantly enhanced sexual desire and lubrication in particular--perhaps because this drug impedes the reuptake of dopamine and noradrenaline.


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Last Update: 7/21/2016