Selective Serotonin Reuptake Inhibitors (SSRIs)
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Introduction
Selective Serotonin Reuptake Inhibitors, commonly referred to as SSRIs, have been recommended by the National Institute for Health and Care Excellence (NICE) as one of the most effective classes of medication for the treatment of generalized anxiety disorder (GAD) [5] . GAD is a common psychiatric disorder which is primarily characterized by an irrational/excessive worry about a number of different events. Key symptoms include excessive anxiety induced by various events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months. Research, which is continually developing in conjunction with more precise mapping of neurotransmitter pathways in the brain, suggests that various abnormalities in serotonergic function can facilitate the pathogenesis of various anxiety disorders. Serotonin is one of the chemical messengers (neurotransmitters) that carries signals between cells in the brain (neurons) and directly influences mood, social behavior, sleep and memory [2]. SSRIs act to ease the positive and negative symptoms of GAD by increasing levels of serotonin in the brain. SSRIs block the reabsorption or reuptake of serotonin molecules in the synapses between neurons in the brain, making serotonin more abundant and readily available. SSRIs are classified as selective neuromodulators, because they aim to primarily act on the serotonergic pathways. This means that they only impact the levels of serotonin and not other neurotransmitters [10]. In the majority of cases in which physicians prescribe a regular regimen of SSRIs, the patient has previously failed to respond to more conservative methods of treatment such as education on the disorder, self-help exercises and lifestyle changes, all of which have shown to help in some capacity in less serious cases of GAD. The most commonly prescribed SSRIs by physicians are Citalopram (20mg) and Prozac (60mg).
Selective Serotonin Reuptake Inhibitors, commonly referred to as SSRIs, have been recommended by the National Institute for Health and Care Excellence (NICE) as one of the most effective classes of medication for the treatment of generalized anxiety disorder (GAD) [5] . GAD is a common psychiatric disorder which is primarily characterized by an irrational/excessive worry about a number of different events. Key symptoms include excessive anxiety induced by various events and issues, and difficulty controlling worrisome thoughts that persists for at least 6 months. Research, which is continually developing in conjunction with more precise mapping of neurotransmitter pathways in the brain, suggests that various abnormalities in serotonergic function can facilitate the pathogenesis of various anxiety disorders. Serotonin is one of the chemical messengers (neurotransmitters) that carries signals between cells in the brain (neurons) and directly influences mood, social behavior, sleep and memory [2]. SSRIs act to ease the positive and negative symptoms of GAD by increasing levels of serotonin in the brain. SSRIs block the reabsorption or reuptake of serotonin molecules in the synapses between neurons in the brain, making serotonin more abundant and readily available. SSRIs are classified as selective neuromodulators, because they aim to primarily act on the serotonergic pathways. This means that they only impact the levels of serotonin and not other neurotransmitters [10]. In the majority of cases in which physicians prescribe a regular regimen of SSRIs, the patient has previously failed to respond to more conservative methods of treatment such as education on the disorder, self-help exercises and lifestyle changes, all of which have shown to help in some capacity in less serious cases of GAD. The most commonly prescribed SSRIs by physicians are Citalopram (20mg) and Prozac (60mg).
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Brief history of SSRIs
Dr. Arvid Carlsson (pictured), a Swedish neuroscientist, was one of the first researchers to pursue a pharmaceutical approach of treatment for anxiety disorders. He was considered a pioneer in the era of development of psychotropics, in which the molecules began to be designed to act on a particular site, receptors, enzymes or reuptake pumps[10]. During this era of psychopharmacological advancement, Carlsson successfully synthesized the antidepressant/anxiolytic compound, zimelidine[4]. Zimelidine was the first drug to specifically target the serotonergic neurotransmitter pathway and modulate levels of serotonin within synapses of the brain, thus being the first drug in the class of SSRIs[4]. Although the original results of Carlsson’s research were first released in 1980, the drug itself, Zelmid, was put on the market two years later at a meeting in Europe in 1982[4]. After its vigorous promotion, the signing of a co-marketing agreement with a major pharmaceutical company in the United States, and subsequent introduction to the pharmaceutical world, Zelmid started to be prescribed by physicians and clinicians at an impressively high rate due to their curiosity of the effects of this novel drug. This curiosity was answered by some unexpected aversive side effects after Zelmid had been administered to the patient. These side effects included nausea and insomnia in patients.
Zelmid appeared to have overwhelmingly positive effects in some patients who hadn’t previously responded to other drugs that had been used to previously treat anxiety. However, in some very serious, yet incredibly rare cases the prescription of Zelmid, the drug produced a serious neurological side effect, Guillian-Barre syndrome, and thus had to be withdrawn from the market. Following this discontinuation of production of Zelmid, five new SSRI antidepressants were designed by five different pharmaceutical companies, including: fluoxetine (Prozac) , fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft) and citalopram (Celexa)[4]. These drugs act on serotonergic neurons, which consequently caused side effects related to serotonin function, including: sexual dysfunction, nausea, incoordination, tremors, akathisia, and in some very rare cases, the serotonin syndrome, which can be fatal if not addressed. Some researchers have warned that a combination of monoamine oxidase (MAO) inhibitors with SSRIs could lead to the development of serotonergic syndrome [8].
Dr. Arvid Carlsson (pictured), a Swedish neuroscientist, was one of the first researchers to pursue a pharmaceutical approach of treatment for anxiety disorders. He was considered a pioneer in the era of development of psychotropics, in which the molecules began to be designed to act on a particular site, receptors, enzymes or reuptake pumps[10]. During this era of psychopharmacological advancement, Carlsson successfully synthesized the antidepressant/anxiolytic compound, zimelidine[4]. Zimelidine was the first drug to specifically target the serotonergic neurotransmitter pathway and modulate levels of serotonin within synapses of the brain, thus being the first drug in the class of SSRIs[4]. Although the original results of Carlsson’s research were first released in 1980, the drug itself, Zelmid, was put on the market two years later at a meeting in Europe in 1982[4]. After its vigorous promotion, the signing of a co-marketing agreement with a major pharmaceutical company in the United States, and subsequent introduction to the pharmaceutical world, Zelmid started to be prescribed by physicians and clinicians at an impressively high rate due to their curiosity of the effects of this novel drug. This curiosity was answered by some unexpected aversive side effects after Zelmid had been administered to the patient. These side effects included nausea and insomnia in patients.
Zelmid appeared to have overwhelmingly positive effects in some patients who hadn’t previously responded to other drugs that had been used to previously treat anxiety. However, in some very serious, yet incredibly rare cases the prescription of Zelmid, the drug produced a serious neurological side effect, Guillian-Barre syndrome, and thus had to be withdrawn from the market. Following this discontinuation of production of Zelmid, five new SSRI antidepressants were designed by five different pharmaceutical companies, including: fluoxetine (Prozac) , fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft) and citalopram (Celexa)[4]. These drugs act on serotonergic neurons, which consequently caused side effects related to serotonin function, including: sexual dysfunction, nausea, incoordination, tremors, akathisia, and in some very rare cases, the serotonin syndrome, which can be fatal if not addressed. Some researchers have warned that a combination of monoamine oxidase (MAO) inhibitors with SSRIs could lead to the development of serotonergic syndrome [8].
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Neurochemical role of SSRIs
SSRIs are referred to as selective because they aim to primarily regulate levels of serotonin, and not interact with other neurotransmitters [3]. Collectively, SSRIs are significantly more potent in terms of their binding affinity for their respective receptors and serotonin pumps relative to their affinity for any other neurotransmitter pumps or neuroreceptors. SSRIs differ from tricyclics, another category of medications commonly used to treat anxiety and depression, because they block only the reuptake pumps for serotonin and not those for norepinephrine[10]. Thus, since SSRIs have fewer nonspecific actions when in the synapse, they will therefore have fewer side effects than tricyclic anxiolytics and antidepressants. SSRIs act to selectively inhibit the reuptake of serotonin within the synapse. Due to this inhibition of reuptake, SSRIs decrease the amount of serotonin that is reabsorbed by the presynaptic neuron. As a result, more of the serotonin originally released from the vesicles of the pre-synaptic neurons remains in the synaptic cleft for a longer time, which compensates for the lower levels of serotonin occurring in those affected by GAD [7]. This leads to an increase in concentration of serotonin molecules and subsequently the chemical signaling across synapses contained within the serotonergic pathways of the brain, in which serotonin serves as the primary neurotransmitter. Upon prolonged prescription, the increased occupancy of the presynaptic 5-HTR serotonin receptors relays signals back to the presynaptic neuron that instruct it to synthesize and release less serotonin into the synaptic cleft[13]. Serotonin levels within the synapse proceed to drop, then rise again, in time leading to a final downregulation of postsynaptic serotonin receptors [13].
SSRIs are referred to as selective because they aim to primarily regulate levels of serotonin, and not interact with other neurotransmitters [3]. Collectively, SSRIs are significantly more potent in terms of their binding affinity for their respective receptors and serotonin pumps relative to their affinity for any other neurotransmitter pumps or neuroreceptors. SSRIs differ from tricyclics, another category of medications commonly used to treat anxiety and depression, because they block only the reuptake pumps for serotonin and not those for norepinephrine[10]. Thus, since SSRIs have fewer nonspecific actions when in the synapse, they will therefore have fewer side effects than tricyclic anxiolytics and antidepressants. SSRIs act to selectively inhibit the reuptake of serotonin within the synapse. Due to this inhibition of reuptake, SSRIs decrease the amount of serotonin that is reabsorbed by the presynaptic neuron. As a result, more of the serotonin originally released from the vesicles of the pre-synaptic neurons remains in the synaptic cleft for a longer time, which compensates for the lower levels of serotonin occurring in those affected by GAD [7]. This leads to an increase in concentration of serotonin molecules and subsequently the chemical signaling across synapses contained within the serotonergic pathways of the brain, in which serotonin serves as the primary neurotransmitter. Upon prolonged prescription, the increased occupancy of the presynaptic 5-HTR serotonin receptors relays signals back to the presynaptic neuron that instruct it to synthesize and release less serotonin into the synaptic cleft[13]. Serotonin levels within the synapse proceed to drop, then rise again, in time leading to a final downregulation of postsynaptic serotonin receptors [13].
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Multiple types of serotonin receptors are found throughout structures in the brain that are known to contribute to the production of fear and anxiety, specifically the hippocampus, cerebral cortex, and raphe nuclei, and the activation of these discrete region leads to both immediate and long-term changes in the chemical balances of them [11]. Research on these serotonergic receptors has lead to the identification of 15 different types, all of which can been divided into seven distinct families, 5-HT1–7. Aside from the 5-HT3 receptor, which is a ligand-gated ion channel, the remaining six families of receptors classify as GPCRs, or G-Protein Coupled Receptors. The 5-HT1A inhibitory autoreceptor is the most expansively researched serotonergic receptor and it is a crucial component of the fear circuitry within our brains that regulates motor and autonomic stress responses, two physiological symptoms of GAD. Anxiety is generally associated with a downregulation of the 5-HT1A receptor in the hippocampus and in the temporal lobe, therefore agonists to this receptor have been found to act as anxiolytics[11]. Similar to the 5-HT1A receptors are the 5-HT1B serotonergic receptors, which are positioned on the axon terminals of retinal ganglion cells in the superior colliculus, our visual startle system, and also on the septal terminals in the hippocampus[11]. Research regarding the 5-HT1B receptor has shown that it is closely involved in the production of aggressive and impulsive behaviors [11]. In conjunction with this receptor, serotonin functions to regulate levels of acetylcholine and also glutamate levels in our brain, two neurotransmitters involved in the physiological stress responses common to GAD, and thus plays a major role in cognitive behavior. A multitude of knockout studies with both of these receptors have been performed, all of which reaffirm the importance of serotonin in the regulation of mood. Additionally, no single family or subtype of receptors within these pathways is solely responsible for the production of psychiatric diseases, including GAD.
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Primary serotonergic pathways and anatomical structures involved in GAD
The above receptor types are all stimulated or inhibited by the presence of serotonin and SSRIs within the synaptic cleft, but how exactly do these molecules of serotonin neurotransmitters reach the synapse in the first place? Serotonin is primarily (up to 95%) synthesized in our gastrointestinal tract, specifically in enterochromaffin cells, whereas only minute amounts are actually produced within the central nervous system[14]. Therefore there must be a physiological pathway that transports and facilitates the secretion of this neurotransmitter in our brains and Central Nervous System. The enteric nervous system, which includes the gastrointestinal tract, is commonly referred to as our body’s “second brain”, containing some 100 million neurons, more than in either the spinal cord or the peripheral nervous system [14]. Regardless of this discrepancy in the location production of serotonin, reciprocal exchange of the neurotransmitter between the central nervous system and other tissues, especially those within the enteric nervous system, appears to be limited. However, small exchanges in serotonin has been seen through the blood-brain barrier, sent from the enteric nervous system. To counteract this lack of serotonergic transport, neuron subpopulations within the brain have a specific set of enzymes that permit the two-step synthesis of serotonin from its precursor, tryptophan [14].
The above receptor types are all stimulated or inhibited by the presence of serotonin and SSRIs within the synaptic cleft, but how exactly do these molecules of serotonin neurotransmitters reach the synapse in the first place? Serotonin is primarily (up to 95%) synthesized in our gastrointestinal tract, specifically in enterochromaffin cells, whereas only minute amounts are actually produced within the central nervous system[14]. Therefore there must be a physiological pathway that transports and facilitates the secretion of this neurotransmitter in our brains and Central Nervous System. The enteric nervous system, which includes the gastrointestinal tract, is commonly referred to as our body’s “second brain”, containing some 100 million neurons, more than in either the spinal cord or the peripheral nervous system [14]. Regardless of this discrepancy in the location production of serotonin, reciprocal exchange of the neurotransmitter between the central nervous system and other tissues, especially those within the enteric nervous system, appears to be limited. However, small exchanges in serotonin has been seen through the blood-brain barrier, sent from the enteric nervous system. To counteract this lack of serotonergic transport, neuron subpopulations within the brain have a specific set of enzymes that permit the two-step synthesis of serotonin from its precursor, tryptophan [14].
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The amino acid tryptophan acts as a precursor to this synthetic process , in which tryptophan hydroxylase adds a hydroxyl group to the precursor, forming 5-HTP (5-hydroxytryptophan). A carboxyl group is then removed from this product by 5-HTP decarboxylase, resulting in 5-HT, which is serotonin [7]. The cell bodies of serotonergic neurons are organized in nine individual clusters within the brain, the majority of them being located in the raphe nucleus of the midbrain, pons as well as the medula. The two most prominent of these clusters are found in the dorsal and medial raphe nuclei, which are highlighted in purple above in Figure 5. The majority of these nuclei are found on or around the general vacinity of the midline of the brain stem, with the axons of both the dorsal and medial raphe nuclei projecting to the cerebral cortex. As well as the cerebral cortex, these nuclei also project to two regions of the brain that play a large role in our behavioral and autonomic response to stressfull/anxiety inducing stimuli: the amygdala and hippocampus [8]. The hippocampus has tonic inhibitory control over the hypothalamic stress-response system and has also been implicated in stress sensitivity and resiliency in relationship to mood and anxiety disorders [5]. The amygdala is responsible for the expression of fear and aggression as well as species-specific defensive behavior, and it plays a role in the formation and retrieval of emotional and fear-related memories [13]. The amygdala projects to a multitude of different brain regions, all of which evoke a unique autonomic response to the relative stimuli. These pathways are displayed in Figure 6.
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Behavioral changes induced by SSRIs
SSRIs target both the positive and negative symptoms of GAD and have been one of the "cleaner" forms of antidepressants, due to their selectivity and ability to act on only a minute number of neurotransmitter pathways. Through their modulation of serotonergic synapses, SSRIs are designed to decrease the characteristic symptomatic effects of GAD of excessive, uncontrollable, often irrational worry, and apprehensive expectations regarding everyday events or activities[6]. However, although serotonin may be the sole neurotransmitter tageted by this drug, it still controls an extensive range of automic functions. and includes side effects of [3]:
SSRIs target both the positive and negative symptoms of GAD and have been one of the "cleaner" forms of antidepressants, due to their selectivity and ability to act on only a minute number of neurotransmitter pathways. Through their modulation of serotonergic synapses, SSRIs are designed to decrease the characteristic symptomatic effects of GAD of excessive, uncontrollable, often irrational worry, and apprehensive expectations regarding everyday events or activities[6]. However, although serotonin may be the sole neurotransmitter tageted by this drug, it still controls an extensive range of automic functions. and includes side effects of [3]:
- sexual dysfunction
- increased risk of coronary heart disease in some
- increased risk of GI bleeding
- discontinuation syndrome
- increased suicide risk in children and adolescents
- complications in pregnancy and breastfeeding
- persistent pulmonary hypertention
- nausea
- dry mouth
- headache
- sleep schedule irregularities
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