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Seda%ve-‐Hypno%c and Anxioly%c Drugs PSYC 3560 Dr. J. Nicol Anxiety • 10-‐30% of Americans will suffer from a significant anxiety disorder at some point in their lives • Anxiety is expressed vary from episodes of panic, phobic avoidance, intrusive thoughts or compulsive behaviours, and nega%ve thinking paOerns • Anxiety is highly comorbid with clinical depression, and there is both neurobiological and pharmacological evidence suggests a common link between them • Most anxiety manifests as a subjec%vely unseOling feeling of concern or worry Connec%ons of the Amygdala The Amygdala • The amygdala is a major component of emo%on processing circuits • The amygdala receives highly processed sensory informa%on about the environment from the thalamus, and primary and associa%on sensory areas, and the hippocampus • These brain areas project to the lateral nucleus of the amygdala • ASer processing, the informa%on is sent to the central nucleus by direct connec%ons, and by indirect connec%ons via the basolateral nucleus • Central nucleus of the amygdala orchestrates the components of fear The Amygdala • Damaging selected brain areas that receive projec%on neurons from the central nucleus can eliminate specific components of the anxiety response • Intracerebral injec%on of various drugs into the amygdala induces anxiety in animals in a number of experimental paradigms • In addi%on to iden%fying the emo%onal significance of events, the amygdala aids in the forma%on of emo%onal memories, some%mes called condi%oned fear, or condi%oned emo%onal response (CER) The Amygdala • The associa%on is formed in the lateral amygdala, which ac%vates the central nucleus, which ac%vates those brain areas responsible for the components of the behavioural response • Ac%va%on of the amygdala elicits emo%onal responses, but the PFC (i.e., OFC, mPFC) and the subgenual ACC exert inhibitory control over behaviour • Anxiety disorders are considered to arise from an imbalance between the ac%vity of the amygdala and the ac%vity of the PFC Role of CRF in Anxiety • Cor%cotropin-‐releasing factor (CRF) is a neuropep%de that controls the neuroendocrine (HPA axis), autonomic, and behavioural responses to stress • HPA axis is ac%vated by the release of CRF from the hypothalamus in response to stress • CRF is responsible for inducing the anterior pituitary to release the stress hormone adrenocor%cotropic hormone (ACTH) into the blood, which in turn increases the release of glucocor%coids (e.g., cor%sol) from the adrenal cortex • CRF also acts as a neurotransmiOer in neural circuits involved in the stress response including the amygdala Role of CRF in Anxiety • Indeed, CRF causes increased anxiety in a number of conflict tests used in animal research paradigms • Direct neuronal applica%on of CRF produces strong excitatory effects in many brain areas that contain significant numbers of CRF receptors • Large numbers of CRF nerve endings and CRF receptors are found in the amygdala (individual differences in the anxiety level may be due to differences in the amount of CRF in the amygdala) • Stress causes a release of CRF in the amygdala, and this is accompanied by a variety of signs of anxiety -‐ many of these effects can be prevented by pretreatment with a CRF antagonist Role of CRF in Anxiety • CRF neurons origina%ng in the central nucleus of the amygdala project to the LC and ac%vate the adrenergic component of the stress response • Infusion of CRF into the LC produces anxiety • Reciprocal connec%ons between the LC and the amygdala provide a mechanism for genera%ng arousal, orien%ng, and responding to fear-‐evoking s%muli • LC is a major cluster of noradrenergic cells in the dorsal pons that project to brain areas that increase vigilance and arousal Role of NE in Anxiety • Electrical recording in the LC shows increased firing when animals are presented with novel s%muli that signal threat • Electrical s%mula%on of the LC or administra%on of the α2-‐autoreceptor antagonist yohimbine induces a wide range of aler%ng and fear responses • Yohimbine also produces panic aOacks in pa%ents with PD or PTSD, but not in healthy controls • Clonidine a α2-‐autoreceptor agonist has an%-‐anxiety effects Role of NE in Anxiety • Clinical studies of pa%ents with a variety of anxiety disorders suggest that abnormal ANS response is a common key feature • NE is a neurotransmiOer released at the target visceral organs during ac%va%on of the SNS • Epinephrine released from the adrenal medulla produces effects that prepare the individual to respond to danger Role of NE in Anxiety • Both NE and epinephrine have a significant role in the forma%on of emo%onal memories that may contribute to anxiety disorders • Modifying NE func%on with drugs may represent a useful treatment for PTSD • It may be possible to interfere with the forma%on of a trauma%c memory by blocking β-‐adrenergic receptors immediately following trauma Drug effects in LC cell firing Role of NE in Anxiety • Some of the therapeu%c effects of anxioly%c drugs can be explained by modula%on of LC firing • Noradrenergic cells in the LC are excited by CRF synap%c input and are inhibited by GABA and 5-‐HT, as well as by s%mula%on of α2-‐ adrenergic somatodendri%c autoreceptors • BDZs enhance the inhibitory func%on of GABA, so reduced LC firing may be responsible for some of the anxioly%c effects of these drugs • Serotonin reuptake blockade would reduce LC firing and some of their an%-‐anxiety effects • Tricyclic an%depressants and MAOIs that are used to treat some anxiety disorders enhance NE func%on, which inhibits firing of LC neutrons by ac%ng on the α2-‐autoreceptors Role of GABA in Anxiety • Several seda%ve-‐hypno%cs enhance the func%on of GABA, causing seda%on and reduced anxiety • Benzodiazepines (BDZs) and barbiturates produce these effects by binding to modulatory sites that are different from the GABA binding site on the receptor complex • BDZs are the most clinically useful GABA modulators, and their neuropharmacology has told us a great deal about the neurochemistry of anxiety Distribu%on of benzodiazepine (BDZ) receptors in the human brain Role of GABA in Anxiety • The importance of GABA is directly shown by the reduc%on in anxiety produced by local administra%on of GABA or the GABA agonist musimol into the amygdala • Conversely, reduced anxiety can be reduced by a BDZ antagonist and also by co-‐administra%on of a GABA antagonist directly into the amygdala • This effect demonstrates the necessity for GABA ac%vity in the anxioly%c effects of BDZs • The amygdala, par%cularly the basolateral nucleus, is clearly an important site media%ng the an%-‐anxiety effects of BDZs Decreased density of BDZ binding sites in pa%ent with PD (right) compared with control (leS) Role of GABA in Anxiety • Pa%ents with PD show less BDZ binding in por%ons of the frontal lobes, and the limbic system • Reduc%ons in BDZ binding have also been found in selected brain areas of individuals with GAD and PTSD • Reduced binding sites may result in failure of GABA inhibi%on leading to uncontrolled panic aOacks, phobias, generalized anxiety, and the hyperarousal associated with PTSD Role of 5-‐HT in Anxiety • The anxioly%c effects of 5-‐HT are demonstrated by the effec%veness of SSRIs, which enhance 5-‐HT func%on, in trea%ng a variety of anxiety disorders • SSRIs desensi%ze terminal 5-‐HT auto receptors in the OFC only aSer a full 8 weeks of treatment (when improvement in symptoms of OCD is seen) • Desensi%zed autoreceptors indicate that more 5-‐HT is released to act on post-‐synap%c 5-‐HT2 receptors • 5-‐HT has a neurotrophic effects during fetal development and is cri%cal for normal development of the anxiety circuitry • The amygdala and the PFC are two brain areas that show serotonin-‐ dependent developmental differences in morphology and ac%vity Role of DA in Anxiety • A modulatory role for dopamine (DA) in anxiety is suggested by the significant DA projec%ons from the VTA to the mPFC (i.e., the mesocor%cal DA pathway) • Administra%on of the anxiety producing drug (β-‐ carboline) increases firing of mesocor%cal dopaminergic neurons and increases DA turnover in the PFC • Enhancement of GABA func%on by a BDZ blocks the anxiety responses to the stressors and to the β-‐ carboline treatment and also prevents DA turnover Role of DA in Anxiety • Dopaminergic projec%ons to the amygdala from the VTA inhibit the normal descending inhibi%on of the mPFC and permit expression of adap%ve anxiety responses • The released DA ac%ng on D1 and D2 receptors in the amygdala reduces the inhibitory control of local GABA interneurons that are ac%vated by the PFC • Decreasing inhibitory control increases amygdala ac%va%on Role of DA in Anxiety • Stressors increase release and turnover of DA in the central and basolateral nuclei of the amygdala, where D1 and D2 receptors are most densely located • Reducing dopaminergic transmission with neurotoxic lesions of the VTA-‐amygdala pathway reduces condi%oned fear and fear-‐poten%ated startle and impairs acquisi%on of avoidance behaviour • Intra-‐amygdala injec%on of D1 receptor agonists increases anxiety responses in a variety of rodent models, and antagonists at the D1 receptor produce anxioly%c effects Drugs for Trea%ng Anxiety • Drugs that are used to relieve anxiety are called anxioly%cs • Many of them belong to the class of seda%ve-‐hypno%cs, which is part of a larger category called CNS depressants • CNS depressants include the barbiturates, the benzodiazepines, and alcohol • Drugs that relieve anxiety oSen produce a calm and relaxed state, with drowsiness and mental clouding, loss of coordina%on, and slowing of reac%on %me • At higher doses they induce sleep, and that is why they are some%mes referred to as hypno%cs Correla%on between behavioural and clinic potency Dose-‐dependent effects of CNS depressants on levels of consciousness Drugs for Trea%ng Anxiety • Primary mechanism of ac%on of the classic seda%ve-‐ hypno%c drugs is to enhance GABA transmission • GABAA receptor complex regulates a Cl-‐ channel that increases Cl-‐ current into the cell and moves the membrane poten%al farther away from the threshold for firing • Thus, GABA agonists produce local hyper-‐polariza%on, or inhibitory postsynap%c poten%al (IPSP) and inhibit cell firing • BDZs and barbiturates have binding sites as part of the GABAA receptor complex and enhance the inhibitory effects of GABA Effects of GABA and diazepam on membrane poten%als and chloride (Cl-‐) influx Drugs for Trea%ng Anxiety • When BDZs bind to their modulatory sites on the GABAA complex, they enhance the effect of GABA by increasing the number of %mes the channel opens • However, in the absence of GABA, the BDZs have no effect on CL-‐ opening • Presence of a BDZ alters the physical state of the receptors, increasing the affinity for GABA so that GABA opens the channels more easily Effects of GABA and diazepam on membrane poten%als and chloride (Cl-‐) influx Drugs for Trea%ng Anxiety • Addi%on of a compe%%ve antagonist prevents the BDZ-‐ induced enhancement of GABA ac%on but not does affect GABA-‐induced hyper polariza%on • In contrast, the addi%on of a GABA antagonist prevents GABA from opening the channel, and the presence of a BDZ has no further effect • The fact that BDZs do not enhance the maximum response to GABA is responsible for their high therapeu%c index (i.e., clinical safety) Barbiturates • Barbiturates also increase the affinity of the GABAA receptor for GABA, however, they increase the dura%on of the opening of GABA-‐ac%vated Cl-‐ channels rather than the number openings • Barbiturates directly open the Cl-‐ channel without GABA, which likely explains why barbiturates can be lethal while BDZs are not Molecular structure of the Barbiturates Side Effects of Barbiturates • Although barbiturates readily induce sleep, it is not a normal, resiul sleep • The anxioly%c effects of these drugs are accompanied by pronounced cogni%ve side effects • When used repeatedly, barbiturates increase the number of liver microsomal enzymes (producing metabolic tolerance and reduced effec%veness) • Pharmacodynamic tolerance occurs when CNS neurons adapt to the presence of the drug and become less responsive with chronic drug use • Mood changes and seda%on seem to show the greatest and most rapid tolerance, but the lethal respiratory-‐depressant ac%on of the drug does not show tolerance at all Margin of Safety Molecular structure of several Benzodiazepines (BDZ) Benzodiazepines (BDZ) • The BDZs were introduced in 1960 and in general have replaced barbiturates • BDZs target anxiety without producing excessive seda%on, they have a low incidence of tolerance, a less severe withdrawal syndrome, and a very safe therapeu%c index Therapeu%c Effects of BDZs • BDZs cannot be used for deep anesthesia, but they are useful of pre-‐surgical anesthesia • The most popular use for BDZs is relief of anxiety • LiOle or no tolerance occurs to the an%-‐anxiety effects • Some of the longer-‐las%ng BDZs are useful hypno%cs -‐ they shorten the %me needed to fall asleep and increase the dura%on of sleep %me • Some BDZs are useful muscle relaxants and others are an%convulsants • Drugs of choice in preven%ng acute alcohol or barbiturate withdrawal symptoms Therapeu%c Effects of BDZs • Notable advantage over barbiturates is the high therapeu%c index • BDZs are also safer than barbiturates because they do not increase the number of liver microsomal enzymes that normally metabolize the drugs • BDZs have a reputa%on for lower probability of physical dependence and abuse (probability of abuse is almost always associated with poly-‐drug use) Second-‐Genera%on Anxioly%cs • Second-‐genera%on anxioly%cs were developed to provide anxiety reduc%on without some of the side effects of the BDZs • Buspirone has unusual characteris%cs because unlike the seda%ve-‐hypno%cs, it does not enhance GABA func%on, but instead acts a par%al agonist of serotonergic 5-‐HT1A receptors • These receptors are found in heavy concentra%on in the limbic system, including the amygdala Second-‐Genera%on Anxioly%cs • Buspirone has several advantages over the BDZs: • Usefulness in trea%ng the depression • Anxiety reduc%on is not accompanied by seda%on, confusion of mental clouding • Safer than the BDZs • Minimum of severe side effects, and fatal overdoses have not been reported • LiOle or no poten%al for recrea%onal use or dependence • No rebound withdrawal syndrome has been reported Abs%nence effect aSer chronic diazepam, but not buspirone An%depressants and Mood Stabilizers PSYC 3560 Dr. J. Nicol Affec%ve Disorders • Mood disorders are among the most common form of mental illness • Major depression and bipolar disorder are the two primary affec%ve disorders • Major depression is characterized by recurring episodes of dysphoria and nega%ve thinking that is also reflected in behaviour • Bipolar disorder is characterized by cyclical mood swings from depression to mania Role of Stress in Depression • Risk factors for mood disorders are biological (e.g., gene%cs) and environmental (e.g., stress) • Both neurobiological studies and family studies indicate that anxiety and depression are closely related • Physiological symptoms associated with anxiety are typically also seen in depression • Intense environmental stress and anxiety oSen precede episodes of depression • Altered paOerns of stress hormone levels are frequently found in people with depression Role of Stress in Depression • In response to stress, mul%ple neurotransmiOers (e.g., NE, ACh, GABA) regulate the secre%on of cor%cotropin-‐ releasing factor (CRF) from the hypothalamus • CRF controls the release of adrenocor%cotropic hormone (ACTH) from the pituitary into the blood • ACTH in turn acts on the adrenal glands to increase secre%on of cor%sol and other glucocor%coids • Among the most consistent neuroendocrine abnormali%es in depressed individuals is abnormal secre%on of cor%sol Abnormali%es in glucocor%coids in depressed pa%ents Role of Stress in Depression • Many depressed pa%ents have elevated levels of cor%sol in response to a greater-‐than-‐normal release of ACTH • Hyper-‐secre%on is most likely due to abnormal regula%on of CRF by the hypothalamus • Studies have found higher-‐than-‐normal levels of CRF in the cerebrospinal fluid (CSF) of depressed pa%ents and increased numbers of CRF-‐producing cells in the hypothalamus in postmortem brain %ssue of depressives Role of Stress in Depression • High level of cor%sol found in depressed pa%ents is characterized by an abnormal circadian rhythm in cor%sol secre%on • Since many depressed individuals have elevated cor%sol, it is not surprising that some fail to respond to dexamethasone challenge • Besides having damaging effects on immune-‐system and organ func%on, glucocor%coids are associated with neuronal atrophy in the hippocampus, leading to cogni%ve impairment, imbalances in the serotonin (5-‐HT) system correlated with anxiety, and hormonal changes associated with depression The Monoamine Hypothesis • The monamine hypothesis originated with the observa%on that reserpine induces depression as side effect in a significant number or pa%ents that take the drug for reducing blood pressure • Reserpine prevents the transport of neurotransmiOers into vesicles, thereby leaving them in the cytoplasm, where monoamine oxidase (MAO) degrades them • Reserpine treatment produces empty vesicles and reduces the levels of the monoamines (i.e., DA, NE, 5-‐HT) • Despite their varied synap%c ac%on, the an%depressant drugs acutely increase the func%on of NE or 5-‐HT, or both The Monoamine Hypothesis • Reduced levels of NE and 5-‐HT metabolites in the CSF, plasma, or urine of depressed pa%ents, indica%ng lowered NE and 5-‐ HT synap%c ac%vity and low u%liza%on of the monoamines • Manic-‐like ac%vity produced by amphetamine and cocaine is correlated with the increase in catecholamines in the synapse • Prolonged use of these drugs causes deple%on of of the monoamines, resul%ng in depression and lethargy • Evidence suggests that there is anatomical and func%onal interac%on between noradrenergic neurons in the LC and serotonergic neurons in the midbrain raphe The Monoamine Hypothesis • The monoamine hypothesis is too simplis%c to account for the complex syndrome of affec%ve disorders, and it fails to resolve several discrepancies • The most important of these is the discrepancy in %me between the rapid neurochemical ac%ons of an%depressants and the slow onset of clinical effects over several weeks • Demonstrates that the acute enhancement of monoamine func%on is not the neurochemical basis for the therapeu%c effects Serotonin Dysfunc%on • The effects of 5-‐HT on sleep, ea%ng, and thermoregula%on seem to contribute to depressive symptoms • Lower 5-‐HIAA levels (metabolite of 5-‐HT) have been found in postmortem brains of depressed individuals • Tryptophan, the 5-‐HT precursor, is another measure of serotonergic func%on that frequently appears low in depressed pa%ents compared to controls • Tryptophan deple%on of unmedicated pa%ents in remission causes a relapse of depression symptoms, and leads to a depressed mood in healthy subjects who have a family history of depression, but not in healthy subjects without that family history Probability of depressive episode is determined an interac%on between genes and the environment Caspi et al. (2003) Serotonin Dysfunc%on • Short allele of the serotonin transporter (SERT) gene has been associated with depression, but the rela%onship occurs only in associa%on with increased stressful life events • Receptor binding sites in postmortem brain samples from unmedicated individuals with mood disorders have found increased density of post-‐synap%c 5-‐HT2 receptors, which could be considered a compensatory response to low serotonergic ac%vity • 5-‐HT receptors are less sensi%ve in depressed pa%ents PET scan of blood flow in the brain of a pa%ent with major depression Effects of an%depressants of serotonergic cells Effects of an%depressants of serotonergic cells Serotonin Dysfunc%on • The increased synap%c 5-‐HT has postsynap%c ac%on but also acts on 5-‐HT autoreceptors to slow the firing rate of cells and to reduce 5-‐HT synthesis and release • Overall, lower neuronal ac%vity reduces metabolism of 5-‐HT to 5-‐HIAA, indica%ng reduced turnover of 5-‐HT • Chronic treatment results in tolerance and reduces the ac%on of the autoreceptor and gradually increases the amount of 5-‐HT in the synapse Serotonin Dysfunc%on • The re-‐uptake transporter blockade is s%ll effec%ve, so the two ac%ons both produce an increase in 5-‐HT • The delay in autoreceptor desensi%za%on and subsequent enhanced 5-‐HT ac%vity may be partly responsible for the delayed therapeu%c effects • The increased synap%c 5-‐HT also down-‐regulates post-‐ synap%c 5-‐HT2A receptors Norepinephrine Ac%vity • One of the most consistent findings regarding catecholamine response to chronic an%depressant treatment is the down-‐ regula%on of β-‐receptors • Yohimbine is an α2-‐autoreceptor antagonist that enhances the an%depressant-‐induced down-‐regula%on of β-‐receptors • Importance of NE to the ac%ons of an%depressant drugs can be demonstrated in pa%ents treated with adrenergic an%depressants (i.e., NE re-‐uptake inhibitors), who show relapse of symptoms if NE synthesis is prevented by deple%on of the NE precursor tyrosine • NE is therefore necessary for those drugs to be effec%ve Anatomical and func%onal overlap of NE and 5-‐HT systems in the brain The Glucocor%coid Hypothesis • The glucocor%coid hypothesis focuses on the stress-‐ related neuroendocrine abnormali%es that are frequently found in depressed individuals • The abnormal secre%on of CRF from the hypothalamus is likely responsible for the hyper-‐sec%on of ACTH from the pituitary, and cor%sol from the adrenal cortex in depressed individuals The Glucocor%coid Hypothesis • The hypothalamic CRF neurons are normally controlled by other areas of the CNS: the amygdala, which is central to emo%onal responses, normally s%mulates the CRF circuit, and the hippocampus has inhibitory control • The hippocampus has receptors that when ac%vated by high levels of glucocor%coids help to inhibit CRF release from the hypothalamus and returning glucocor%coid levels to normal • Intense and/or prolonged stress causes glucocor%coid levels remain high, and hippocampal neurons are damaged The Glucocor%coid Hypothesis • Damage includes decreases in dendri%c branches and loss of dendri%c spines, both of which occur in the PFC and the hippocampus • Elevated cor%sol reduces forma%on of new hippocampal cells (neurogenesis) • Elevated cor%sol levels found in depressed individuals could contribute to cell death and to some of the cogni%ve symptoms of depression • The glucocor%coid hypothesis of affec%ve disorders is the basis for the clinical tests of CRF receptor antagonists, which did show early promise as an%depressants The Neurotrophic Hypothesis • The neurotrophic hypothesis suggests that low brain-‐ derived neurotrophic factor (BDNF) is be responsible for the loss of dendri%c and spines in the hippocampus and PFC and for reduced neurogenesis in the hippocampus • An%depressants may protect vulnerable cells by preven%ng the decrease in BDNF • Chronic an%depressant treatment increases BDNF in both humans and animals, and an%depressants prevent stress-‐induced reduc%ons in BDNF and neuronal atrophy Effect of stress and an%depressant treatment on BDNF in hippocampal cells An%depressant Medica%ons • Three major classes of an%depressants have proved effec%ve in reducing symptoms of mood disorders: • Monoamine oxidase inhibitors • Tricyclic an%depressants • Second-‐genera%on an%depressants (e.g., SSRIs) • Each drug is effec%ve in reducing symptoms for about two-‐ thirds of cases of clinical depression • The different pharmacological characteris%cs of the drugs mean that they reduce different symptoms and produce dis%nct side effects An%depressant Medica%ons • Each drug is effec%ve in reducing symptoms for about two-‐thirds of cases of clinical depression • The different pharmacological characteris%cs of the drugs mean that they reduce different symptoms and produce dis%nct side effects • Every one of the treatment methods requires chronic administra%on, sugges%ng that although we understand how each works acutely at the synapse, the clinical effect must depend on compensatory changes in func%on that require %me to develop An%depressant Medica%ons • Treatment requires chronic administra%on, sugges%ng that the clinical effect must depend on compensatory changes in func%on that require %me to develop • Significant changes in symptoms occur during the first 1-‐3 weeks of drug treatment, maximum effec%veness not achieved un%l aSer 4-‐6 weeks of therapy • An%depressant drugs reduce the anxiety that accompanies depression, and they are increasingly being used to treat anxiety disorders unrelated to depression Monoamine Oxidase Inhibitors • Iproniazid was used in the 1950s to treat tuberculosis but had significant mood-‐eleva%ng effects, and it was determined that it inhibited monoamine oxidase • Despite their early promise, the MAOIs fell into disfavour because of their reputa%on for having severe and dangerous side effects • With appropriate dietary restric%ons, MAOIs can be used safely and oSen work well for pa%ents who are treatment-‐resistant Acute and long-‐term effects of MAOIs on synap%c func%on Monoamine Oxidase Inhibitors • The inhibi%on of the MAO enzyme increases the amount of neurotransmiOer available for release • MAO increases NE, DA, and 5-‐HT and thus increases the ac%on of the transmiOers at their receptors • The biochemical changes occur within hours, but the an%depressant effects require weeks of chronic treatment • Neuron adapta%on involving change in receptor density or second-‐messenger func%on plays an important part in these drug effects Tricyclic An%depressants Tricyclic An%depressants • The drugs in this class act by binding to the presynap%c transporter proteins and inhibi%ng re-‐uptake of neurotransmiOers in the presynap%c terminal • Inhibi%on of re-‐uptake prolongs the dura%on of transmiOer ac%on at the synapse, ul%mately producing changes in the pre-‐ and post-‐ synap%c receptors • As was true for the MAOIs, the immediate increase in NE and 5-‐ HT func%on in not correlated with clinical effec%veness, which takes several weeks • Clearly, an acute increase in synap%c ac%vity is only the first step in an%depressant ac%on; neuronal adapta%on, occurring over a period of %me, also plays an important role Tricyclic An%depressants • The drugs in this class are equally effec%ve in inhibi%ng the re-‐uptake of NE and 5-‐HT, but some are more effec%ve on one transmiOer than the other • Although this difference does not change their an%depressant ac%on, it does determine the side effects of the drugs • In addi%on to re-‐uptake blockade, most of the TCAs block ACh, histamine, and α-‐adrenergic receptors, and this contributes to their side effects Tricyclic An%depressants • Histamine receptor blockade is responsible for the seda%on and fa%gue that are frequent side effects • The α1 blockade in combina%on with the NE re-‐uptake-‐ blocking effects leads to several poten%ally dangerous cardiovascular side effects • These drugs have a rela%vely low therapeu%c index, par%cularly when used by pa%ents demonstra%ng suicidal tendencies Second-‐Genera%on An%depressants • Designed to be more selec%ve in their ac%on with the hope of elimina%ng the an%-‐cholinergic and cardiovascular effects produced by older drugs while s%ll eleva%ng levels of NE and/or 5-‐HT to provide an%depressant ac%on • SSRIs are oSen the first choice among an%depressants because of their rela%vely greater safety • Drugs in this class are more selec%ve than TCAs in enhancing serotonin func%on because they block the presynap%c repute transporter for 5-‐HT to a greater extent than the noradrenergic transporter Second-‐Genera%on An%depressants • Although the an%depressant ac%on may be related to increased 5-‐HT func%on at some serotonergic receptors, increased 5-‐HT ac%vity at other receptors causes side effects • One dis%nc%ve characteris%c of the SSRIs compared with older an%depressants is their ability to cause physical dependence Mood Stabilizers • Lithium carbonate is the most effec%ve medica%on and is the usual drug of choice for pa%ents with bipolar disorder • One to two weeks of lithium use eliminates or reduces symptoms in about 60-‐80% of manic episodes without causing depression or producing seda%on • Less effec%ve in termina%ng episodes of depression, so it is oSen administered along with an an%depressant • Most important is that it is useful for reducing the occurrence of future episodes of mania and depression Effec%veness of Lithium Carbonate for trea%ng Bipolar disorder Mood Stabilizers • Lithium enhances 5-‐HT ac%ons: it elevates brain tryptophan, 5-‐HT, and 5-‐HIAA, and increases 5-‐HT release, which ul%mately alters receptor response in several brain areas • It reduces catecholamine ac%vity by enhancing reuptake and reducing release • Lithium modifies synap%c transmission at points beyond the neurotransmiOer receptors (e.g., in second-‐messenger func%on) • The therapeu%c index of lithium is very low, and a pa%ents blood level of lithium must be monitored on a regular basis
