Abstract Background There is a great individual difference of antidepressant response. Whether neuroplasticity plays a role for this difference,. Aim To discuss the potential role of neuroplasticity for difference in antidepressant efficacy. Methods A search of literature with an emphasis on neuroplasticity and antidepressant efficacy variances. Results The development of central nervous system is affected by coactions of both genetics and environment. Enriched environment significantly improves the brain growth and brain damage repair. Hostile growth environment including chronic stresses, depression and mood disorder weakens neuroplasticity. Different individuals have different neuroplasticity. Even monozygotic twins may develop different neuroplasticity. Recent evidences suggest that antidepressants act by enhancing neuroplasticity, which allows environmental inputs to modify the neuronal networks to better fine tune the individual to the outside world. There is a great individual difference of antidepressant response. Conclusions Variance of neuroplasticity in the depressive patients may play a role for individual difference of antidepressant efficacy.
Keywords Neuroplasticity · Antidepressant · Individual difference
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Impact of finding on practice
Neuroplasticity may play a role for antidepressant efficacy.
Physicans need to aware that assessment of neuroplasticity might be helpful for dosage adjustment of antidepressants.
Introduction
Neuroplasticity is the changing of neurons, their networks organization, and their function via new experiences. This idea was first proposed in 1890 by William James in The Principles of Psychology, though the idea was largely neglected for the next fifty years[1]. The brain consists of neurons and glial cells which are interconnected. All areas of the brain are plastic even after childhood. For example, although ocular dominance columns in the lowest neocortical visual area, V1, are largely immutable after the critical period in development, environmental changes could alter behavior and cognition by modifying connections between existing neurons and via neurogenesis in the hippocampus and other parts of the brain, including the cerebellum. Many researches have shown that substantial changes occur in the lowest neocortical processing areas, and that these changes can profoundly alter the pattern of neuronal activation in response to experience.
According to the theory of neuroplasticity, thinking, learning, and acting actually change both the brain’s physical structure (anatomy) and functional organization (physiology). Neuroscientists are presently engaged in a reconciliation of critical period studies demonstrating the immutability of the brain after development with the new findings on neuroplasticity, which reveal the mutability of both structural and functional aspects[2].
Methods
Literature with an emphasis on neuroplasticity and antidepressant efficacy variances was collected using PubMed. Papers published in languages other than English were excluded before screening. Completeness of literature was not a primary aim but general coverage was nevertheless controlled for to some extent by comparing the papers we identified and used with those identified in published review papers.
Variance of neuroplasticity among people
The development of central nervous system is affected by coactions of both genetics and environment. Enriched environment significantly improve the brain growth and brain damage repair[3]. Hostile growth environment including chronic stresses and depression mood disorder weakens neuroplasticity. A hypothesis was proposed that expression of neuroplasticity is a form of adaptation based on natural selection, where cells deprived of sensory input actively go and look for information in order to survive. Neural circuits are shaped by experience in early postnatal life. Distinct GABAergic connections within visual cortex determine the timing of the critical period for rewiring ocular dominance to establish visual acuity.
Different individuals have different degrees of neuroplasticity. Even monozygotic twins may develop different neural structure and neuroplasticity, though they share the identical gene background. The estimated number of human protein-coding genes is around 35,000. Meanwhile each hemisphere of human brain occupies about 1011 neurons, let alone the hundreds of connections that each neuron makes. This suggested that human genes contain too little information to specify neural system and there must be an important random factor in neural development. Cortical laminar development exhibits a process that is mathematically consistent with a random walk with drift. Cerebral cortex has a range of interconnected functional architectures. Some appear random and without structure, while others are geometrical. Additionally, epigenetic factors play a role in neural development, which will lead to different expressions of a gene. These are evidenced by discordance in some diseases morbidity as following examples. An investigation showed significant hippocampal atrophy was detected in the demented twins compared with the controls. Meanwhile in the non-demented twins, only a minor, non-significant reduction was observed in the hippocampal volumes compared with the controls. This suggests gene-environment interactions that have protected the non-demented twins longer than their demented co-twins and contributed to the relative preservation of their hippocampal volumes. Some monozygotic twins are discordant in many diseases such as bulimia nervosa, schizophernia, bipolar disorders, and sexual orientation.
Depression weakens neuroplasticity
Depression is a common mood disorder defined by characteristic signs and symptoms, severity, and duration. The cause is believed to be multifactorial, with genetic, temperamental, behavioral, and environmental risk factors interacting with one another at critical developmental periods. Depressive patients usually display many neruo-biochemical and neuro-physiological changes.
First, depression could be characterized by low serum brain-derived neurotrophic factor (BDNF ) levels, which suggests that neurotrophic factor is involved in affective disorders. Serum levels of BDNF in depressive patients are significantly decreased compared with normal controls. BDNF is a critical mediator of activity-dependent neuroplasticity in the cerebral cortex. The deficits in neurotrophic factors have been proposed to underlie mood disorders. Low levels of neurotrophins may not directly produce depression, but indirectly through abnormality in the adaptation of neural networks to environmental conditions.
Second, depression, at least in its severe form, is associated with reduced volumes of the hippocampus and prefrontal cortex[4]. Stress-induced neuronal damage might affect neurogenesis in the hippocampus, which is thought to be involved in the pathogenesis of mood disorders. People with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss. One study compared hippocampal function and hippocampal volumes in depressed people experiencing a postpubertal onset of depression. Depressive people with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset[5].
Adult hippocampal neurogenesis is a critical form of cellular plasticity that is greatly influenced by neural activity. Serotonin and norepinephrine are two neurotransmitters that are widely implicated in regulating this process; their levels are modulated by stress, depression and clinical antidepressants. Norepinephrine but not serotonin directly activates self-renewing and multipotent neural precursors, including stem cells, from the hippocampus of adult mice. These findings suggest that the activation of neurogenic precursors and stem cells via ?3-adrenergic receptors could be a potent mechanism to increase neuronal production, providing a putative target for the development of novel antidepressants[6].
Besides the hippocampus, the basolateral complex of the amygdala (BLA) has been implicated in both basal and stress-induced changes in neuroplasticity in the dentate gyrus. One study suggests that amygdala play a role on hippocampal cell survival and on the neuroplasticity[7].
A new model of depression links the cytokine hypothesis with the neurocircuitry hypothesis. According to the neurocircuitry hypothesis, failure of homeostatic synaptic plasticity in cortical-striatal-limbic nodes is responsible for core symptoms of depression: loss of interest or pleasure (anhedonia) and depressed mood (sadness). According to the cytokine hypothesis, inflammatory cytokines act on neural circuits to evoke the behavioral and physiological changes observed in depression. Synthesis of these hypotheses implicates cytokines as a cause of dysregulated synaptic plasticity in cortical-striatal-limbic circuits[8].
Antidepressants target on neuroplasticity
Clinical and basic researches demonstrate that chronic antidepressant treatment increases the rate of neurogenesis in the adult hippocampus. Antidepressants up-regulate cAMP and the neurotrophin signaling pathways involved in plasticity and survival. In vitro and in vivo data provide direct evidence that the transcription factor, cAMP response element-binding protein (CREB) and the neurotrophin, BDNF are key mediators of the therapeutic response to antidepressants. Depression maybe associated with a disruption of mechanisms that govern cell survival and neuroplasticity in the brain[9].
New research in animals is beginning to change radically our understanding of the biology of stress and the effects of antidepressant agents. Recent findings from the basic neurosciences to the pathophysiology of depressive disorder suggest that stress and antidepressants have reciprocal actions on neuronal growth and vulnerability (mediated by the expression of neurotrophin) and synaptic plasticity (mediated by excitatory amino acid neurotransmission) in the hippocampus and other brain structures. Stressors have the capacity to progressively disrupt both the activities of individual cells and the operating characteristics of networks of neurons, while antidepressant treatments act to reverse such injurious effects[10]. Antidepressant drugs increase the expression of several molecules, which are associated with neuroplasticity; in particular the neurotrophin BDNF and its receptor TrkB. Antidepressants also increase neurogenesis and synaptic numbers in several brain areas. SSRI antidepressant fluoxetine can reactivate developmental-like neuroplasticity in the adult visual cortex, which, under appropriate environmental guidance, leads to the rewiring of a developmentally dysfunctional neural network[11, 12].
As mentioned earlier, one study found that the BLA modulates the effects of fluoxetine on hippocampal cell proliferation and survival in relation to a behavioral index of depression-like behavior (forced swim test). They used a lesion approach targeting the BLA along with a chronic treatment with fluoxetine, and monitored basal anxiety levels given the important role of this behavioral trait in the progress of depression. Chronic fluoxetine treatment had a positive effect on hippocampal cell survival only when the BLA was lesioned. Both BLA lesions and low anxiety were critical factors to enable a negative relationship between cell proliferation and depression-like behavior. This study stressed a role for the amygdala on fluoxetine-stimulated cell survival. It also revealed an important modulatory role for anxiety on cell proliferation involving both BLA-dependent and -independent mechanisms. The findings underscored the amygdala as a potential target to modulate antidepressants action in hippocampal neurogenesis and in their link to depression-like behaviors[7].
Antidepressants may act by enhancing neuroplasticity, which allows environmental inputs to modify the neuronal networks to better fine tune the individual to the outside world. Recent observations in the visual cortex directly support this idea. According to the network hypothesis of depression, neurotrophin may act as critical tools in the process whereby environmental conditions guide neuronal networks to better adapt to the environment. Antidepressants may indirectly produce an antidepressant effect by high levels of neurotrophin. Therefore antidepressant drugs should not be used alone but should always be combined with rehabilitation to guide the plastic networks within the brain[13].
Individual difference in antidepressant efficacy
Are antidepressants truly effective in all patients? Meta-analysis of all available trials of each antidepressant in the treatment of major depressive disorders, including treatment resistant depression and long-term relapse prevention is conduced by many reserachers[14-16]. The efficacy and safety of antidepressants vary significantly. New evidences showed that the total effective rate of fluoxetine was about 77%[17]. Various classes of antidepressant medications generally induce remission of major depressive disorder in only about one-third of patients. One double-blind study suggested the superiority of different combinations of antidepressant drugs from treatment initiation. 105 patients meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive, from treatment initiation, either fluoxetine monotherapy (20 mg/day) or mirtazapine (30 mg/day) in combination with fluoxetine (20 mg/day), venlafaxine (225 mg/day titrated in 14 days), or bupropion (150 mg/day) for 6 weeks. The primary outcome measure was the Hamilton Depression Rating Scale (HAM-D) score. The overall dropout rate was 15%, without notable differences among the four groups. Compared with fluoxetine monotherapy, all three combination groups had significantly greater improvements on the HAM-D. Remission rates (defined as a HAM-D score of 7 or less) were 25% for fluoxetine, 52% for mirtazapine plus fluoxetine, 58% for mirtazapine plus venlafaxine, and 46% for mirtazapine plus bupropion[18].
Although the use of antidepressants increased markedly during the 1990s, in recent years it has decreased as a result of concerns regarding the emergence of suicide during antidepressant treatment. There is evidence that selective serotonin reuptake inhibitors (SSRIs) can improve adolescent depression better than placebo, although the magnitude of the antidepressant effect is ‘small to moderate’, because of a high placebo response, depending the different individual. A cautious and well-monitored use of antidepressant medications is a first-line treatment option in adolescents with moderate to severe depression. Low rates of remission with current treatment strategies indicate that further research in both psychotherapy and pharmacotherapy is warranted[19].
Conclusions
There is a great efficacy individual difference of antidepressants. Meanwhile there is a different degree of neuroplasticity in depressive patients. We propose that the variance of neuroplasticity may play a role in individual difference of antidepressant efficacy.
Conflicts of interest statement: This work was supported by a foundation of Southern Medical University.
