The earliest written descriptions of a relationship between mania and melancholia are attributed to Aretaeus of Cappadocia. Aretaeus was an eclectic medical philosopher who lived in Alexandria somewhere between 30 and 150 AD. Aretaeus is recognized as having authored most of the surviving texts referring to a unified concept of manic-depressive illness, viewing both melancholia and mania as having a common origin in black bile. Emil Kraepelin (1856-1926), a German psychiatrist categorized and studied the natural course of untreated bipolar patients long before mood stabilizers were discovered. Describing these patients in 1902, he coined the term manic depressive psychosis. Kraepelin, however, divided the “manic states” into four forms—hypomania, acute mania, delusional mania, and delirious mania He noted in his patient observations that intervals of acute illness, manic or depressive, were generally punctuated by relatively symptom-free intervals in which the patient that was able to function normally. mil Kraepelin (15 February 1856 – 7 October 1926) was a German psychiatrist. H.J. Eysenck's Encyclopedia of Psychology identifies him as the founder of modern scientific psychiatry, as well as of psychopharmacology and psychiatric genetics. Kraepelin believed the chief origin of psychiatricdisease to be biological and genetic malfunction The earliest written descriptions of a relationship between mania and melancholia are attributed to Aretaeus of Cappadocia. Aretaeus was an eclectic medical philosopher who lived in Alexandria somewhere between 30 and 150 AD. Aretaeus is recognized as having authored most of the surviving texts referring to a unified concept of manic-depressive illness, viewing both melancholia and mania as having a common origin in black bile. Emil Kraepelin (1856-1926), a German psychiatrist categorized and studied the natural course of untreated bipolar patients long before mood stabilizers were discovered. Describing these patients in 1902, he coined the term manic depressive psychosis. He noted in his patient observations that intervals of acute illness, manic or depressive, were generally punctuated by relatively symptom-free intervals in which the patient that was able to function normally. In 1949, John Cade discovered that lithium carbonate could be used as a successful treatment of manic depressive psychosis In the 1950s, U.S. hospitals began experimenting with lithium on their patients. By the mid-1960s, reports started appearing in the medical literature regarding lithium's effectiveness. The U.S. Food and Drug Administration did not approve of lithium's use until 1970.
Mood can be normal, elevated, or depressed.Mood can be normal, elevated, or depressed. Psychopharmacology became an integral part of psychiatry starting with Otto Loewi's discovery of the neuromodulatory properties of acetylcholine; thus identifying it as the first-known neurotransmitter. Neuroimaging was first utilized as a tool for psychiatry in the 1980s. The discovery of chlorpromazine's effectiveness in treating schizophrenia in 1952 revolutionized treatment of the disease, as did lithium carbonate's ability to stabilize mood highs and lows in bipolar disorder in 1948. Psychotherapy was still utilized, but as a treatment for psychosocial issues. Following Sigmund Freud's death, ideas stemming from psychoanalytic theory also began to take root. The psychoanalytic theory became popular among psychiatrists because it allowed the patients to be treated in private practices instead of warehoused in asylums The name "melancholia" comes from the old medical belief of the four humors: disease or ailment being caused by an imbalance in one or other of the four basic bodily liquids, or humors. Personality types were similarly determined by the dominant humor in a particular person. According to Hippocrates, melancholia was caused by an excess of black bile, hence the name, which means 'black bile', from Ancient Greek μέλας (melas), "dark, black", + χολή (kholé), "bile"; a person whose constitution tended to have a preponderance of black bile had a melancholic disposition. See also: sanguine,phlegmatic, choleric. Melancholia was described as a distinct disease with particular mental and physical symptoms in the 5th and 4th centuries BC. Hippocrates, in hisAphorisms, characterized all "fears and despondencies, if they last a long time" as being symptomatic of melancholia. When a patient could not be cured of the disease it was thought that the melancholia was a result of demonic possession
Bipolar disorder is a cyclical mood disorder Abnormally elevated mood or irritability alternates with depressed mood bipolar I – at least one manic or mixed episode bipolar II – at least one major depressive episode and at least one hypomanic episode Bipolar I – one or more manic episodes and one or more depressive episodes Bipolar II – at least one hypomanic episode and one or more episodes of major depression Bipolar disorders less prevalent than unipolar, .8-1.6% of population age of onset in 20s Rapid cycling depression/mania – 4 or more episodes per year Cyclothymia = hypomania with “minor” depression “Bipolar spectrum” = Depression + other complexities Bipolar NOS or Mood DO NOS
In current nomenclature, those patients whose manic episodes never pass beyond the stage of hypomania are said to have “Bipolar II” disorder, in contrast with “Bipolar I” disorder wherein the mania does escalate beyond the hypomanic stage. Recent data indicate that bipolar II disorder may be more common than bipolar I disorder; however, should a patient with bipolar II disorder ever have a manic episode wherein stage II or III symptoms occurred, then the diagnosis would have to be revised to bipolar I.
Several lines of evidence point to a role of dopamine (DA) system in mood disordersD2: the predominant subtype in the brain: regulates mood, emotional stability in the limbic system and movement control in the basal ganglia. Many lines of evidence point to the aberrant increased activity of the dopaminergic system as being critical in the symptomatology of schizophrenia. There is a greater occupancy of D2 receptors by dopamine => greater dopaminergic stimulation. Antipsychotics reduce dopamine synaptic activity. These drugs produce Parkinson-like symptoms. Drugs that increase DA in the limbic system cause psychosis. Drugs that reduce DA in the limbic system (postsynaptic D2 antagonists) reduce psychosis. Increased DA receptor density (Post-mortem, PET). Changes in amount of homovanillic acid (HVA), a DA metabolite, in plasma, urine, and CSF
vesicular monoamine transporter protein (VMAT2) was quantified with (+)[11C]dihydrotetrabenazine (DTBZ) and PET (38). Sixteen asymptomatic BD-I patients who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than in the comparison subjectsvesicular monoamine transporter protein (VMAT2) was quantified with (+)[11C]dihydrotetrabenazine (DTBZ) and PET (38). Sixteen asymptomatic BD-I patients who had a prior history of mania with psychosis (nine men and seven women) and individually matched healthy subjects were studied. VMAT2 binding in the thalamus and ventral brainstem of the bipolar patients was higher than in the comparison subjects
study on the central cholinesterase inhibitor physostigmine (administered intravenously), in which transient modulation of symptoms in manic cases and induction of depression in euthymic bipolar patientsMuch of the evidence supporting the involvement of the cholinergic system in mood disorders comes from neurochemical, behavioral and physiologic studies in response to pharmacologic manipulations CHOLINERGIC DOPA-The highest levels of D2 dopamine receptors are found in the striatum, the nucleus accumbens, and the olfactory tubercle. D2 receptors are also expressed at significant levels in the substantia nigra, ventral tegmental area, hypothalamus, cortical areas, septum, amygdala, and hippocampus CHOLINERGIC-in the treatment of mania—probably due to their poor tolerability and pharmacokinetics—there is sufficient evidence to conclude that activation of the cholinergic muscarinic system may produce antimanic activity. We propose that this antimanic activity is mediated by stimulation of muscarinic M4 receptors (Table 3).8,14–16,74–77 Muscarinic M4 receptors are found in high density in limbic and cortical structures.8 Furthermore, they are negatively coupled to adenylate cyclase and, like the mood stabilizers, decrease cAMP formation.74 Decreases in signal transduction through the cAMP system and subsequent effects on kinases would therefore be expected to have prominent effects on stabilizing potential anomalous neurotransmission in limbic and cortical target regions for mania. Mice with the muscarinic M4 receptor ablated have been shown to have increased locomotor activity and enhanced response to dopamine agonist-induced behaviors, such as amphetamine-induced locomotion. 14 InIn contrast, M4-preferring muscarinic agonists, such as PTAC, BuTAC and xanomeline, functionally block dopamine agonist-induced behaviors, like apomorphine-induced climbing, without possessing appreciable affinity for dopamine receptors. 15,16,75,76 Xanomeline and PTAC also acutely and chronically block dopamine cell firing selectively in the A10 dopamine pathways that project to the limbic and cortical areas. Xanomeline has recently been shown to increase extracellular dopamine levels and Fos expression in prefrontal cortex, similar to olanzapine, suggesting cortical activation.77 Thus, M4 receptors are in high density in the appropriate brain regions purported to be affected in bipolar disorder, and they have the same effects on signal transduction as mood stabilizers. Similar to dopamine antagonists used for the treatment of mania, they functionally antagonize hyperactive dopamine tracts in limbic areas. Finally
Postmortem studies have shown an increased NE turnover in the cortical and thalamic areas of BD subjects (12,13), whereas in vivo studies have found plasma levels of NE and its major metabolite, 3-methoxy-4-hydroxyphenylglycol (MHPG), to be lower in bipolar than unipolar depressed patients, and higher in bipolar patients when manic than when depressed (3,11). The same occurs with urinary MHPG levels, which are lower in bipolar depressed patients, while longitudinal studies show that MHPG excretion higher in the manic compared to depressed state (3,4,10,11). Finally, in a consistent mode, cerebrospinal fluid (CSF) NE and MHPG are also reported to be higher in mania than in depression
Glutamate, the most abundant excitatory neurotransmitter, is integral for synaptic transmission in brain circuitry, and is a key regulator of synaptic strength and plasticity, which play major roles in the neurobiology of learning, memory and general cognition . Altered glutamate levels in plasma, serum and cerebrospinal fluid have been observed in human studies of individuals with mood disorders . Moreover, NMR spectroscopy studies have shown altered levels of glutamate and related metabolites in diverse brain regions of patients with bipolar disorder
The biosynthetic pathway for glutamate involves synthesis from glucose and the transamination of α-ketoglutarate; however, a small proportion of glutamate is formed more directly from glutamine by glutamine synthetase. The latter is synthesized in glia and, via an active process (requiring ATP), is transported to neurons where glutaminase converts this precursor to glutamate. In astrocytes, glutamine is oxidized to α-ketoglutarate which can also be transported to neurons and participate in glutamate synthesis. Glutamate is either metabolized or it is sequestered and stored in secretory vesicles by vesicular glutamate transporters (VGluTs). Glutamate is then released by a calcium-dependent excitotoxic process. Once released from the presynaptic terminal, glutamate binds to many excitatory amino acid DU et al. Page 19 Neuron Glia Biol. Author manuscript; available in PMC 2009 October 19. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript (EAA) receptors, including ionotropic (e.g. AMPA and NMDA) and metabotropic receptors. Presynaptic regulation of glutamate release occurs through metabotropic glutamate receptors (mGluR2/3), which act as autoreceptors. However, these receptors are also located on the postsynaptic element. The action of glutamate is terminated in the synapse by reuptake mechanisms that utilize distinct transporters (GLUTs) which exist on presynaptic nerve terminals and astrocytes. Current data indicate that astrocytic uptake of glutamate might be more important for clearing excess glutamate, raising the possibility that astrocytic loss (as documented in mood disorders) might contribute to deleterious glutamate signaling. It is known that there several intracellular proteins alter the function of glutamate receptors
Peripheral blood studies have also confirmed these findings and widened the understanding of the relationship between the functioning of G proteins and mood states. Schreiber et al37 were the first to evidence an increase in the activity of G protein in mononuclear leucocytes of manic patients. Other two studies observed increase in mononuclear Gs levels of non-medicated depressed bipolar patients,38-39 whereas other study found increased levels in manic and decreased levels in depressive state.40 Besides, this increase in Gs expression was also demonstrated in platelets,41-42 but not in lymphoblasts.43 These studies suggest that mood state and cell type may influence in the finding of increased Gs in the peripheral blood of bipolar subjects. Taken as a whole, these findings suggest a possible association of the functioning of G proteins in the pathophysioloy of DB. However, it has still not been determined if BD is associated with direct dysfunction in the activity of G proteins or these findings represent a secondary manifestation of a dysfunction in other pathways…………………………………………………………..induction of de-novo gene expression. Most of the extracellular agents bind to membranal receptors, and do not penetrate the cells in order to activate transcription. Rather, the extracellular signals are transferred from the membranes to the genes in the nucleus via several communication lines known as intracellular signaling pathways, which operate within a complex network. In many cases, the transmission of signals
One of the effector proteins regulated by G proteins is adenilate cyclase (AC), an enzyme which catalyzes the formation of cAMP, an important second messenger, from adenosine triphosphate (ATP – see Figure 2). One of the main functions of cAMP is the activation of other enzyme, a cAMP-dependent protein kinase (PKA), which integrates the fast neurotransmission alterations in long-term neurobiological alterations. Several studies demonstrated a significant increase in the activity of basal and activated AC among BD subjects, and these alterations may be associated with the dysfunction of G proteins Phosphatidylinositol (PIP2) pathway Several neurotransmission systems use the phophatidylinositol pathway (Table 1) through the activation of G proteins. In this pathway, G protein activation stimulates the phospholipase C effector protein (PLC), which hydrolyzes a membrane phospholypide, called phosphatidylinositol (PIP2), forming two important second messengers: diacilglycerol (DAG) and inositol triphosphate (IP3). IP3 has a specific receptor situated in the smooth endoplasmatic reticulum which releases Ca+2 stocks whenever activated. DAG, inhas the function of activating protein kinase C. In order to maintain the transmission efficiency of this pathway, the cell needs to keep an adequate supply of inositol for the re-synthesis of PIP2. As inositol crosses weakly the blood brain barrier, its supply is provided by dephosphorylation of IP3, through catalization by inositol monophosphatase (IMPase). Shimon et al59 compared brains of bipolar, suicide subjects and controls and showed a significant decrease in free inositol in the frontal cortex of bipolar and suicide subjects when compared to the control group, but did not find alterations in IMPase activity on that regionPKC is an important enzyme in the PIP2 pathway, acting on the regulation of the neuronal excitability, release of neurotransmitters, genic expression and synaptic plasticity.1The ratios of platelet membrane-bound to cytosolic PKC activities were elevated . Increased PKC activity and translocation in BD brains Elevated levels of selected PKC isozymes in cortices with BD subjects dramatically reduce the hippocampal levels of a major PKC substrate, MARCKS (myristoylatedalanine rich C kinase substrate), which has been implicated in regulating long-term neuroplastic events TAMOFIXEN
Print patho-Protein kinase C (PKC) exists as a family of closely related subspecies, has a heterogenous distribution in brain (with particularly high levels in presynaptic nerve terminals), and, together with other kinases, appears to play a crucial role in the regulation of synaptic plasticity and various forms of learning and memory PKC signaling pathway GLU GLU GLU GLU GLU The PKC family of enzymes is a group of calcium- and phospholipid-dependent enzymes that comprise a family of closely related kinase subspecies and appears to play a crucial role in regulating synaptic plasticity and various forms of learning and memory (Stabel and Parker, 1991; Nishizuka, 1992; Newton, 1995; Nishizuka, 1995). PKC is one of the major intracellularsignal mediators that is generated after external stimulation of cells via several neurotransmitter receptors (including acetylcholine M1, M3 and M5 receptors, α1 adrenoceptors, metabotropic glutamate receptors and serotonin 5HT2A receptors), which induce the hydrolysis of various membrane phospholipids. Recent evidence indicates that alterations in PKC activity might play a significant role in mood disorders. Friedman et al. (1993) investigated PKC activity and PKC translocation in response to serotonin in platelets obtained from bipolar disorder patients before and during lithium treatment. They report that the ratio of platelet-membrane-bound:cytosolic PKC activity is elevated in manic subjects. In addition, serotonin-elicited platelet PKC translocation is enhanced in these subjects. Wang and Friedman (1996) measured PKC isozyme levels, activity and translocation in postmortem brain tissue from bipolar disorder patients. They report increased PKC activity and translocation in bipolar disorder brains compared with controls, accompanied by elevated levels of selected PKC isozymes in the cortex. Evidence from several groups demonstrates clearly that therapeutically relevant concentrations of lithium exert significant effects on the PKC signaling cascade. Data indicate that chronic treatment with lithium attenuates PKC activity and down-regulates the expression of isozymes PKCα and PKCε in the frontal cortex and hippocampus of patients with bipolar disorder (Manji and Lenox, 1999; Manji and Lenox, 2000b). Chronic lithium also dramatically reduces the hippocampal levels of a major PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS), which has a role in regulating long-term neuroplastic events. To validate the therapeutic relevance of these biochemical findings, it is noteworthy that the structurally-dissimilar antimanic agent VPA produces similar effects to lithium on PKC α and PKC ε isozymes and the MARCKS protein (Manji and Lenox, 1999; Manji and Lenox,Data indicate that chronic treatment with lithium attenuates PKC activity and down-regulates the expression of isozymes PKCα and PKCε in the frontal cortex and hippocampus of patients with bipolar disorder (Manji and Lenox, 1999; Manji and Lenox, 2000b). Chronic lithium also dramatically reduces the hippocampal levels of a major PKC substrate, myristoylated alanine-rich C kinase substrate (MARCKS), which has a role in regulating long-term neuroplastic events………
Wnt proteins bind to G-protein binding membrane receptors (frizzled), activating the disheveled protein kinase, which inhibits the glycogen synthase kinase 3 (GSK3-) activityAmong these activities, stands out the modulation of proteins associated with cytoskeleton microtubules, such as tau, MAP-1B and MAP-2, and the regulation of programmed cell death (apoptosis).73 The phophorylation of tau and MAP-1B by GSK3- is associated with the loss or destabilization of microtubules’ conformation75,76 and the use of lithium showed to decrease the phosphorylation of tau in human neuron culture.77 GSK3- is directly associated with the increase in neuronal apoptosis,74 decreasing the activities of proteins which promote the neuronal survival, such as cAMP response element binding protein (CREB) and the heat shock factor-1 (HSF- 1).78-79 Besides, lithium, valproate and lamotrigine protected SHSY5Y cells from apoptosis facilitated by GSK3-.80 GSK3- activity may be modulated by a series of i
Post-mortem brain studies have also revealed changes that might reflect possible ‘signatures’ of abnormal Ca2+ homeostasis in bipolar disorder. These include a marked blunting of Gprotein- activated PI hydrolysis (Jope et al., 1996) and altered mRNA expression of two candidate proteins that might have important roles in Ca2+ homeostasis. These are inositol monophosphatase (IMPase) type II (Yoon et al., 2001a) and a transient receptor potential channel, TRPM2 (TRPC7 in earlier nomenclature) (Yoon et al., 2001b), which is a ligandgated plasma membrane ion channel that also mediates Ca2+ entry into cells. In addition, lithium and VPA inhibit IMPase (Hallcher and Sherman, 1980), which has been suggested to diminish overactive signaling through PI-linked second messengers and, in turn, Ca2+ (Berridge et al., 1982). intracellular Ca2+ in peripheral cells in BD (54,75). These studies have consistently revealed elevations in both resting and stimulated intracellular Ca2+ levels in platelets, lymphocytes and neutrophils of patients with BD. The regulation of free intracellular Ca2+ is a complex, multi-faceted process, and the abnormalities observed in BD could arise from abnormalities at a variety of levels (54). Ongoing studies should serve to delineate the specific regulatory sites at which the impairment occurs in BD.PRINT PATHO Glu glu glu -Calcium ions play a crucial role in regulating the synthesis and release of neurotransmitters, neuronal excitability and long-term neuroplastic events and, therefore, it is not surprising that several studies have investigated the role of intracellular Ca2+ in peripheral cells in bipolar disorder. Intracellular Ca2+ signaling and homeostasis are maintained by an intricate array of processes that act in concert including, for example, inositol trisphosphate (IP3)- and ryanodine-stimulated release of Ca2+ from ER storage pools, voltage- and ligand-gated ionchannel- mediated Ca2+ influx, store-operated Ca2+ entry, plasma membrane Ca2+–ATPase pumps, sarcoplasmic–ER Ca2+–ATPase pumps, and mitochondrial Ca2+ uptake, storage and release (reviewed by Pisani et al., 2004). Regardless of the complexity of intracellular Ca2+ regulation, impaired regulation of Ca2+ cascades is the most reproducible biological abnormality described in bipolar disorder research. For this reason, mechanisms involved in Ca2+ regulation are postulated to underlie aspects of the pathophysiology of bipolar disorder. To date, cumulative studies consistently revealed elevations in basal intracellular Ca2+ concentrations in platelets, lymphocytes and neutrophils of patients with bipolar disorder (Emamghoreishi et al., 1997). Post-mortem brain studies have also revealed changes that might reflect possible ‘signatures’ of abnormal Ca2+ homeostasis in bipolar disorder. These include a marked blunting of Gprotein- activated PI hydrolysis (Jope et al., 1996) and altered mRNA expression of two candidate proteins that might have important roles in Ca2+ homeostasis. These are inositol monophosphatase (IMPase) type II (Yoon et al., 2001a) and a transient receptor potential channel, TRPM2 (TRPC7 in earlier nomenclature) (Yoon et al., 2001b), which is a ligandgated plasma membrane ion channel that also mediates Ca2+ entry into cells. In addition, lithium and VPA inhibit IMPase (Hallcher and Sherman, 1980), which has been suggested to diminish overactive signaling through PI-linked second messengers and, in turn, Ca2+ (Berridge et al., 1982). In summary, mood disorders are associated with alterations in signaling networks that might, subsequently, regulate synaptic plasticity and cell resilience of neuronal circuitry associated with affective disorders. It is noteworthy that modulation of synaptic plasticity by signaling cascades has been studied extensively in the glutamatergic system, specifically for α-amino-3- hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor trafficking
Hyperactivity of hpa.is the end product of the HPA axis, which comprises the hypothalamus, pituitary gland and adrenal cortices (Figure I). Neurosecretory cells within the paraventricular nucleus of the hypothalamus secrete corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the circulatory system of the pituitary. This causes release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary, which leads to cortisol release from the adrenals. Cortisol has numerous cellular effects, which are mediated via the GR and the mineralocorticoid receptor (MR). The hippocampus regulates the endocrine system stress system by modulating hypothalamic paraventricular nucleus activity. Chronic dysregulation of the HPA axis in response to stress is associated with impaired glucocorticoid function and inhibition of negative feedback via the GR . Importantly, reduced levels of GR have been observed in patients with bipolar disorder or depression. Considerable evidence shows that stress exposure is associated with mood disorder development. Dysregulated HPA axis activation probably plays a key role in mood disorder development because stress-induced neuronal atrophy is prevented by adrenalectomy [99,100]. This is noteworthy given that a significant percentage of patients with mood disorders display some manifestations of HPA axis dysfunction, and patients with HPA axis dysfunction are most likely to be associated with volumetric reductions in the hippocampus [3,99,100]. A significant effect of long-term exposure to excessive glucocorticoids is a reduction in cellular resiliency, rendering neurons more vulnerable to other noxious insults, including excitotoxicity and oxidative stress [3,91,131]. Whether varying intracellular signaling cascades, particularly those associated with neuroprotective and neurotrophic signaling cascades, within the- stress response system can provide resiliency or attenuate susceptibility to stressful stimuli remains an open question. Ongoing and future studies aimed at targeting BAG-1, which mediates GR trafficking, may help to determine whether these interventions can provide resiliency from GR-related stress effects
its gradual acceptance worldwide by the 1960s, and late official acceptance in the U.S. in 1970Lithium
Serotonin (SE or 5-HT) is an inhibitory afferent projection to dopamine (DA) nuclei in the ventral tegmentum area (VTA) and substantia nigra, pars compacta (SNc). Lithium, paroxetine, and mCPP increase the SE inhibitory input to VTA and SNc nuclei but through different mechanisms of action: Lithium facilitates SE release. Paroxetine blocks SE reuptake. mCPP is a 5-HT2B/2C agonist. These actions decrease DA neuronal activity and hence DA release in its terminal projections. The decreased DA release amplifies the DA deficiency produced by the perphenazine blockade of DA receptors
Li+ modifies some hormonal responses mediated by adenylyl cyclase or PLC in other tissues, including the actions of vasopressin and thyroid-stimulating hormone on their peripheral target tissues Li+ can inhibit the effects of receptor-blocking agents that cause supersensitivity in such systems. In part, the actions of Li+ may reflect its ability to interfere with the activity of both stimulatory and inhibitory G proteins (Gs and Gi) by keeping them in their inactive trimeric state SECOND MECHANISM In general, these show that lithium increases basal levels of cyclic AMP but impairs receptorcoupled stimulation of cyclic AMP production (Figure 3). One hypothesis is that these dual effects of lithium are due to inhibition by lithium of the G-proteins that mediate cyclic AMP production. Receptor-mediated production of cyclic AMP is controlled by a stimulatory G-protein, Gs, and a counter-balancing inhibitory G-protein, Gi. Under basal conditions, cyclic AMP production is tonically inhibited by the prevailing Gi influence. Increased basal cyclic AMP levels caused by lithium may occur at least in part because lithium reduces the activity of Gi, apparently by shifting its equilibrium between a free active conformation and an inactive heterotrimeric conformation towards the inactive form,5,66,88–90 but not all studies find such inhibitory effects.91 Therefore, inhibitory effects of lithium on Gi can elevate the basal level of cyclic AMP
THIRD-Li+ treatment also leads to consistent decreases in the functioning of protein kinases in brain tissue, including PKC, particularly isoforms and (Jope, 1999; Manji and Lenox, 2000; Quiroz et al., 2004). Among other proposed antimanic or mood-stabilizing agents, this effect is also shared with valproic acid (particularly for PKC) but not with carbamazepine (Manji and Lenox, 2000). Long-term treatment of rats with lithium carbonate or valproate decreases cytoplasm-to-membrane translocation of PKC and reduces PKC stimulation–induced release of 5-HT from cerebral cortical and hippocampal tissue. Excessive PKC activation can disrupt prefrontal cortical regulation of behavior, but pretreatment of monkeys and rats with lithium carbonate or valproate blocks the impairment in working memory induced by activation of PKC in a manner also seen with the PKC inhibitor chelerythrine (Yildiz et al., 2008). The impact of Li+ or valproate on PKC activity may secondarily alter the release of amine neurotransmitters and hormones as well as the activity of tyrosine hydroxylase (Manji and Lenox, 2000). A major substrate for cerebral PKC is the myristolated alanine-rich C-kinase substrate (MARCKS) protein, which has been implicated in synaptic and neuronal plasticity. The expression of MARCKS protein is reduced by treatment with both Li+ and valproate, but not by carbamazepine, antipsychotic medications, or antidepressants (Watson and Lenox, 1996). This proposed mechanism of PKC inhibition has been the basis for therapeutic trials of tamoxifen, a selective estrogen receptor modulator that is also a potent centrally active PKC inhibitor (Einat et al., 2007). In acutely manic bipolar I patients, tamoxifen has shown evidence of efficacy as adjunctive treatment, and in two double-blind, placebo-controlled monotherapy trials (Yildiz et al., 2008; Zarate et al., 2007). inositol monophosphatase and interference with the phosphatidylinositol pathway (Figure 16–1), leading to decreased cerebral inositol concentrations (Williams et al., 2002). Phosphatidylinositol (PI) is a membrane lipid that is phosphorylated to form phosphatidylinositol bisphosphate (PIP2). Activated phospholipase C cleaves PIP2 into diacylglycerol and inositol 1,4,5- trisphosphate (IP3), with the latter stimulating Ca2+ release from cellular stores. IP3 is dephosphorylated to inositol monophosphate (IP) and thence to inositol by inositol monophosphatase. Within its range of therapeutic concentrations, Li+ uncompetitively inhibits this last step (Chapter 3), with resultant decrease in available inositol for resynthesis into PIP2 (Shaldubina et al., 2001). The inositol depletion effect can be detected in vivo with magnetic resonance spectroscopy (Manji and Lenox, 2000). A recent genome-wide association study has implicated diacylglycerol kinase in the etiology of bipolar disorder, strengthening the association between Li+ actions and PI metabolism (Baum et al., 2008). Further support for the role of inositol signaling in mania rests on the finding that valproate, and valproate derivatives, decrease intracellular inositol concentrations lithium inhibits an unidentified kinase that phosphorylates glycogen synthase,102 which was later identified as glycogen synthase kinase-3b and recently shown to be the kinase directly inhibited by lithium.101 Several recent studies found that inhibition of glycogen synthase kinase-3b by lithium reduces tau phosphorylation. 101,103–107 The majority of these studies have been conducted by investigators interested in developmental effects of glycogen synthase kinase-3b or microtubule dynamics, rather than lithium’s therapeutic effects, so acute treatments and supra-therapeutic concentrations of lithium, generally 5–20 mM, were utilized Both Li+ and valproate treatment also inhibit the activity of glycogen synthase kinase-3 (GSK-3) (Williams et al., 2002). Of relevance to mood disorders, GSK-3 inhibition increases hippocampal levels of -catenin, a function implicated in mood stabilization (Kozikowski et al., 2007). GSK-3 has been found to regulate mood stabilizer-induced axonal growth and synaptic remodeling and to modulate brain-derived neurotrophic factor response. Mice with mutant forms of the GSK-3 gene demonstrate abnormalities of biological rhythms that are proposed endophenotypes for the circadian disruption seen in manic patients. In animal models, Li+ induces molecular and behavioral effects comparable to that seen when one GSK-3 gene locus is inactivated. Potent and selective GSK-3 inhibitors show expected activity in mouse models of mania, thus providing further stimulus for exploring this mechanism (Kozikowski et al., 2007). Another proposed common mechanism for the actions of Li+ and valproate relates to reduction in arachidonic acid turnover in brain membrane phospholipids (Rao et al., 2008). Rats fed Li+ in amounts that achieve therapeutic CNS drug levels have reduced turnover of PI ( 83%) and phosphatidylcholine ( 73%); chronic intraperitoneal valproate achieves reductions of 34% and 36%, respectively. Li+ also decreased gene expression of PLA2 and decreased levels of COX-2 and its products (Rapoport and Bosetti 2002).
FOURTH MECH Dephosphorylation of tau at the glycogen synthase kinase-3b sites, which is caused by lithium, enhances the binding of tau to microtubules, which promotes microtubule assembly.108 Therefore, this action of lithium suggests that it may stabilize microtubule-based neuronal structureBoth Li+ and valproate treatment also inhibit the activity of glycogen synthase kinase-3 (GSK-3) (Williams et al., 2002). Of relevance to mood disorders, GSK-3 inhibition increases hippocampal levels of -catenin, a function implicated in mood stabilization (Kozikowski et al., 2007). GSK-3 has been found to regulate mood stabilizer-induced axonal growth and synaptic remodeling and to modulate brain-derived neurotrophic factor response. Mice with mutant forms of the GSK-3 gene demonstrate abnormalities of biological rhythms that are proposed endophenotypes for the circadian disruption seen in manic patients. In animal models, Li+ induces molecular and behavioral effects comparable to that seen when one GSK-3 gene locus is inactivated. Potent and selective GSK-3 inhibitors show expected activity in mouse models of mania, thus providing further stimulus for exploring this mechanism (Kozikowski et al., 2007). Inhibition of glycogen synthase kinase-3b (GSK-3b) by lithium modulates the phosphorylation and function of the microtubule-associated proteins tau and MAP-1B. GSK- 3b phosphorylates tau (t), which decreases its binding to microtubules, and phosphorylates MAP-1B, which increases its binding to microtubules. By inhibiting GSK-3b, lithium decreases the phosphorylation of tau and MAP-1B, increasing tau microtubule binding and decreasing MAP-1B microtubule binding. Although each binds microtubules, tau and MAP-1B are not functionally interchangeable and each of their actions may predominate in different neuronal compartments
FIFTH MECH-Another proposed common mechanism for the actions of Li+ and valproate relates to reduction in arachidonic acid turnover in brain membrane phospholipids (Rao et al., 2008). Rats fed Li+ in amounts that achieve therapeutic CNS drug levels have reduced turnover of PI ( 83%) and phosphatidylcholine ( 73%); chronic intraperitoneal valproate achieves reductions of 34% and 36%, respectively. Li+ also decreased gene expression of PLA2 and decreased levels of COX-2 and its products (Rapoport and Bosetti 2002 This hypothesis was derived largely from studies in unanesthetized rats chronically administered FDAapproved mood stabilizers, as well as the clinically-proven ineffective topiramate for comparison. Lithium, carbamazepine and sodium valproate were shown to downregulate AA turnover in brain phospholipids, without changing DHA or palmitic acid turnover. Lamotrigine reduced AA incorporation coefficients k* in brain phospholipids. The effect on AA turnover of lithium and carbamazepine was ascribed to reduced expression of AA-selective cPLA2 and of its AP-2 transcription factor, whereas valproate's effect was ascribed to its inhibition of an AA-selective microsomal acyl-CoA synthetase Each of the four agents depressed rat brain COX-2 expression and, when measured, the concentration of the COX-2 - derived AA metabolite, PGE2. Topiramate, which had been proposed as a mood stabilizer based on initial trials, but later failed Phase III trials, did not alter any brain AA cascade marker. Thus, the AA cascade hypothesis corresponds to proven clinical efficacy of the tested drugs lithium can inhibit phospholipase A2, an enzyme that mediates the production of arachidonate. 115,116 Since arachidonate can contribute to the activation of protein kinase C, it was suggested that its reduced production after lithium may contribute to reduced activation of protein kinase The first level is at the neuroreceptor itself, the second its coupling mechanism with cPLA2. cPLA2 also can be transcriptionally downregulated by drug action on its transcription factor, AP-2 (lithium and carbamazepine), whereas reincorporation of AA can be slowed by drug inhibition of an AA-selective acyl-CoA synthetase (valproate). These effects are correlated with reduced turnover of AA in membrane phospholipids. Drugs also can inhibit formation of PGE2 and/or TXB2 by downregulating activity and/or transcription of COX-2 (and expression of NF-κB) and COX-1 respectively. See Text and Table 4 for detailed effects. Adapted from (Rao et al., 2008). More functional information may be gained from examining transcription factor DNA binding activity. This was first employed only in 1995, but is now receiving much attention. Stimulation of AP-1 DNA binding activity in rat brain was found not only to be attenuated by lithium, but also to be influenced by circadian rhythm.129 This attenuation of stimulated AP-1 by lithium was confirmed in cultured cells, but elevated basal AP-1 DNA binding activity was noted as the concentration of lithium was increased.125,130 Lithium also increased basal AP-1 in several cultured cell lines and in rat brain, although with evidence of differential lithium concentration sensitivities among cell types.126,128,131 The opposite actions of lithium on stimulated (decrease) and basal (increase) AP-1 DNA binding activity at first appeared to be contradictory. However, these have been proposed to reflect actions of lithium at different sites which are cellularly integrated to reduce the magnitude of fluctuations in AP- 1, and consequently of AP-1-responsive gene expression, so after lithium treatment minimal basal levels are elevated and maximal stimulated levels are
nuclear regulatory factors that affect gene expression (e.g., AP-1, AMI-1, PEBP-2; both agents increase expression of Bcl-2, which is associated with protection against neuronal degeneration/apoptosis (Manji and Chen, 2002
Virtually complete within 6–8 hours; peak plasma levels in 30 minutes to 2 hours Distribution: in total body water; slow entry into intracellular compartment. Initial volume of distribution is 0.5 L/kg, rising to 0.7–0.9 L/kg; some sequestration in bone. No protein binding. Excretion: virtually entirely in urine. Lithium clearance about 20% of creatinine. Plasma half-life about 20 hours Target plasma concentration: 0.6–1.4 mEq/L Dosage: 0.5 mEq/kg/d in divided doses Lithium is readily and nearly completely absorbed in the gastrointestinal tract. Peak concentrations occur within 2 to 4 hours of administration of immediate release formulations. Slow release formulations are associated with later and lower peak concentrations. 6 Lithium is not metabolized; approximately 95% is renally excreted.
Renal excretion can be increased by administration of osmotic diuretics or acetazolamideLithium toxicity is dose related Lithium is minimally protein bound The therapeutic dose is 300-2700 mg/d with desired serum levels of 0.7-1.2 mEq/L. Lithium clear via kidneys. increased risk of renal toxicity with metronidazole, verapamil. Most filtered lithium is reabsorbed in the PCT Diuretics acting distally to the proximal tubule, such as thiazides and spironolactone Reabsorption of lithium is increased and toxicity is more likely in patients who are hyponatremic or volume depleted, both of which are possible consequences of diuretic therapyLoop diuretics may increase serum lithium levels and potentiate the risk of lithium toxicity. The exact mechanism is unknown but may be related to the sodium loss induced by loop diuresis, which produces a compensatory increase in proximal tubular reabsorption of sodium along with lithium.
Acceptably safe are between 0.6 and 1.5 mEq/L. 1.0-1.5 mEq/L- acutely manic or hypomanic patients. 0.6-1.0 mEq/L long-term prophylaxis. 0.8-1.0 mEq/L experience decreased relapse risk Individualization of serum levels is often necessary to obtain a favorable risk-benefit relationship The concentration of Li+ in blood usually is measured at a trough of the daily oscillations that result from repetitive administration (i.e., from samples obtained 10-12 hours after the last oral dose of the day). Peaks can be two or three times higher at a steady state. When the peaks are reached, intoxication may result, even when concentrations in morning samples of plasma at the daily nadir are in the acceptable range of 0.6-1 mEq/L. Single daily doses generate relatively large oscillations of plasma Li+ concentration but lower mean trough levels than with multiple daily dosing, and are associated with a reduction in the extent and risk for polyuria (Schou et al., 1982); moreover, single nightly dosing means that peak serum levels occur during sleep, so complaints regarding CNS adverse effects are minimized.
The occurrence of toxicity is related to the serum concentration of Li+ and its rate of rise following administration The more serious effects involve the nervous system and include mental confusion, hyperreflexia, gross tremor, dysarthria, seizures, and cranial nerve and focal neurological signs, progressing to coma and death.
Sodium polystyrene sulfonate (SPS, Kayexalate), a cation exchanger, has been promising in animal models and human reports to reduce absorption and enhance elimination of Li.
A 600-mg loading dose of Li+ can be given to hasten the time to steady state, and can also be used to predict dosage requirements based on the 24-hour serum Li+ result, with a very high correlation coefficient. Li+ is effective in acute mania, but is rarely employed as a sole treatment for reasons noted above, and because 5-7 days are required for clinical effect. A 600-mg loading dose of Li+ can be given to hasten the time to steady state, and can also be used to predict dosage requirements based on the 24-hour serum Li+ result, with a very high correlation coefficient (r = 0.972) (Cooper et al., 1973). Acutely manic patients may require higher dosages to achieve therapeutic serum levels, and downward adjustment may be necessary once the patient is euthymic. When adherence with oral capsules or tablets is an issue, the liquid Li+ citrate can be used. Each 5 mL of lithium citrate syrup provides 8.12 mEq of Li+, equivalent to 300 mg of lithium carbonate.
structure similar to that of the tricyclic antidepressant imipramine. 1974- as anti seizure agent Partial tonic clonic seizure Carbamazepine exposure in cultured sensory neurons alters the dynamic behavior of neuron growth cones, effects that are remediated through inositol supplementation, implicating inositol depletion as a mechanism underlying carbamazepine's mood stabilizing properties (Williams
The metabolism of carbamazepine may be inhibited by propoxyphene, erythromycin, cimetidine, fluoxetine, and isoniazid Phenobarbitalythr , phenytoin, valproate may increase the metabolism of carbamazepine by inducing CYP3A4; carbamazepine may enhance the biotransformation of phenytoinHalf-life: 15-30 hrs initially, 10-15 hrs maintenance Metabolism: CYP3A3/4; protein binding significant Maintenance therapeutic range: 4-12 ug/ml drawn at 12 hrs after last dose, minimum of 5 days after last dose change (much variation in what is a therapeutic level from patient to patient?). Narrow therapeutic index. Dosage: per serum level or clinical effect (anywhere from 400-1400 mg/day) Its use may reduce the effectiveness of other drugs metabolised through the same system including other anticonvulsants, hormonal contraceptives and neuroleptics. The teratogenic effects of carbamazepine are discussed below. It is, therefore, particularly important that effective contraceptive measures are taken, and higher doses of hormonal contraceptives or alternative methods of birth control should be used. Some SSRIs and nefazodone may slow the metabolism of carbamazepine through inhibition of cytochrome P450 3A4, potentially precipitating toxic effects17
The initial treatment requires assessment of electrolytes and initial doses from 600 to 1200 mg/day may suffice or should be augmented to 1400 to 2400 mg/day in order to obtain the desired effect.12 Contrarily to CBZ, it does not interfere in the metabolism of other anticonvulsants, but reduces the plasmatic levels of felodipine, verapamil and estrogens among women who take oral anticonceptives
adverse effects such as dizziness or ataxia, even within the therapeutic range (6-12 g/mL) (Post et al., 2007 Carbamazepine response rates are lower than those for valproate compounds or Li+, with mean rates of 45-60% cited in the literature (Post et al., 2007) . Due to increased risk of Stevens-Johnson syndrome in Asian individuals (especially those from China, Hong Kong, Malaysia, and the Philippines where HLA-B*1502 prevalence is > 15%), HLA testing must be performed prior to treatment in populations at risk
Carbamazepine is also teratogenic. Overdose with carbamazepine can be lethal. Activated charcoal can bind to carbamazepine remaining in the gut, and laxatives can facilitate elimination.17 In cases of massive overdose, peak plasma concentrations may not occur for 2 to 3 days after ingestion.9 Acute intoxication with carbamazepine can result in stupor or coma, hyperirritability, convulsions, and respiratory depression. During long-term therapy, the more frequent untoward effects of the drug include drowsiness, vertigo, ataxia, diplopia, and blurred vision. The frequency of seizures may increase, especially with overdosage. Other adverse effects include nausea, vomiting, serious hematological toxicity (aplastic anemia, agranulocytosis), and hypersensitivity reactions (dangerous skin reactions, eosinophilia, lymphadenopathy, splenomegaly). A late complication of therapy with carbamazepine is retention of water, with decreased osmolality and concentration of Na+ in plasma, especially in elderly patients with cardiac disease. Some tolerance develops to the neurotoxic effects of carbamazepine, and they can be minimized by gradual increase in dosage or adjustment of maintenance dosage. Various hepatic or pancreatic abnormalities have been reported during therapy with carbamazepine, most commonly a transient elevation of hepatic transaminases in plasma in 5-10% of patients. A transient, mild leukopenia occurs in ~10% of
Half-life: the parent compound is rapidly and extensively metabolized to a monohydroxy derivative (MHD), which is responsible for the therapeutic effect; MHD is eliminated with a half-life of about 8-10 h Metabolism: ~ 27% of the dose is recovered in the urine as unchanged MHD and a further 49% as a glucuronide conjugate of MHD. It appears that the kinetics of OCB should not be affected by impaired liver function. Impaired kidney function does not affect the kinetics of MHD, but the glucuronide conjugate will accumulate in these patients. Maintenance therapeutic range: N/A; it is unclear if eventually serum levels will be useful Dosage: 800-1800mg/day. When converting from CBZ to OCB, multiply CBZ dose by 1.5 to get an approximately equivalent OCB dose. The initial treatment requires assessment of electrolytes and initial doses from 600 to 1200 The most common ones are headache, somnolence, dizziness and nausea; OXC may cause dose-dependent hyponatremia, evident among 2.5% of patients and more frequent than with CB xcarbazepine is a structural derivative of carbamazepine, with a ketone in place of the carbon–carbon double bond on the dibenzazepine ring at the 10 position (10-keto). This difference helps reduce the impact on the liver of metabolizing the drug, and also prevents the serious forms of anemia oragranulocytosis occasionally associated with carbamazepine. Aside from this reduction in side effects, it is thought to have the same mechanism as carbamazepine – sodium channel inhibition (presumed to be the main mechanism of action) – and is generally used to treat the same conditions. Oxcarbazepine is a prodrug which is activated to eslicarbazepine in the live
simple branched-chain carboxylic acid. Certain other branched-chain carboxylic acids have potencies similar to that of valproic acid in antagonizing pentylenetetrazol-induced convulsions. However, increasing the number of carbon atoms to nine introduces marked sedative properties. Straight-chain carboxylic acids have little or no activity It is frequently administered as valproate sodium in which the valproic acid has been neutralized with sodium hydroxide.
GSK-3 inhibition increases hippocampal levels of -catenin, a function implicated in mood stabilization (Kozikowski et al., 2007). GSK-3 has been found to regulate mood stabilizer-induced axonal growth and synaptic remodeling and to modulate brain-derived neurotrophic factor response
Half-life: 6-16 hrs SUBSTRATE suggested the maintenance of serum levels between 50 and 120 mcg/ Metabolism: beta-oxidation (CYP metabolism is minor); protein binding significant The vast majority of valproate (95%) undergoes hepatic metabolism, with < 5% excreted unchanged in urine. Its hepatic metabolism occurs mainly by UGT enzymes and -oxidation. Valproate is a substrate for CYP2C9 and CYP2C19, but metabolism by these enzymes accounts for a relatively minor portion of its elimination. Some of the drug's metabolites, notably 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid, are nearly as potent anti-seizure agents as the parent compound; however, only the former (2-en-valproic acid) accumulates in plasma and brain to a potentially significant extent. The t1/2 of valproate is ~15 hours but is reduced in patients taking other anti-epileptic drugs Maintenance therapeutic range: 50-125 ug/ml drawn at 12 hrs after last dose, minimum of 4 days after last dose change. For cyclothymia, lower blood levels may be therapeutic. Dosage: per serum level (anywhere from 500-3000 mg/day). For cyclothymia, lower doses may be effective.
G AND G -sodium valproate provides more rapid antimanic effects than Li+, with therapeutic benefit seen within 3-5 days. The most common form of valproate in use is divalproex sodium, preferred over valproic acid due to lower incidence of GI and other adverse effects. Divalproex is initiated at 25 mg/kg once daily and titrated to effect or the desired serum concentration. Serum concentrations of 90-120 g/mL show the best response in clinical studies (Bowden et al., 2006). With immediate release forms of valproic acid and divalproex sodium, 12-hour troughs are used to guide treatment. With the extended-release divalproex preparation, patients respond best when the 24-hour trough levels are in the high therapeutic range (Bowden et al., 2006
G AND G -The most common side effects are transient GI symptoms, including anorexia, nausea, and vomiting in ~16% of patients. Effects on the CNS include sedation, ataxia, and tremor; these symptoms occur infrequently and usually respond to a decrease in dosage. Rash, alopecia, and stimulation of appetite have been observed occasionally and weight gain has been seen with chronic valproic acid treatment in some patients. Valproic acid has several effects on hepatic function. Elevation of hepatic transaminases in plasma is observed in up to 40% of patients and often occurs asymptomatically during the first several months of therapy. A rare complication is a fulminant hepatitis that is frequently fatal (Dreifuss et al., 1989). Pathological examination reveals a microvesicular steatosis without evidence of inflammation or hypersensitivity reaction Valproate competes with some anticonvulsants such as carbamazepine and lamotrigine for hepatic drug-metabolising enzymes, raising their plasma levels. It may enhance the anticoagulant effects of warfarin. In summary, valproate is increasingly frequently prescribed for bipolar disorder and is the leading mood stabiliser in the US. Its effects against mania are established, but its antidepressant and prophylactic effects remain unproven. It has fewer problematic drug interactions than carbamazepine. .
Initially developed as an antifolate agent based on the incorrect idea that reducing folate would effectively combat seizures Lamotrigine (LAMICTAL, others) is a phenyltriazine derivative initially developed as an antifolate agent based on the incorrect idea that reducing folate would effectively combat seizures. Structure-activity studies indicate that its effectiveness as an anti-seizure drug is unrelated to its antifolate properties (Macdonald and Greenfield. Lamotrigine has just been approved by the FDA for "the maintenance treatment of adults with Bipolar I Disorder to delay the time to occurrence of mood episodes (depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy." Although the approval refers to "mood episodes," the data are only convincing for prevention of depression — it does not do well at preventing recurrences of mania. Although there is data supporting its use in acute mania, it seems not to be as reliable for this as valproate, lithium, or olanzapine, and there have even been case reports
Half-life: 25-33 hrs alone (with CBZ 12-15 hrs; with VPA 48-70 hrs) Metabolism: glucuronication then renal excretion; protein binding ~55% (displacement effects are probably negligible) Lamotrigine is completely absorbed from the gastrointestinal tract and is metabolized primarily by glucuronidation. The plasma t1/2 of a single dose is 24-30 hours. Administration of phenytoin, carbamazepine, or phenobarbital reduces the t1/2 and plasma concentrations of lamotrigine. Conversely, addition of valproate markedly increases plasma concentrations of lamotrigine, likely by inhibiting glucuronidation. Addition of lamotrigine to valproic acid produces a reduction of valproate concentrations by ~25% over a few weeks. Concurrent use of lamotrigine and carbamazepine is associated with increases of the 10,11-epoxide of carbamazepine and clinical toxicity in some patients
Maintenance therapeutic range: not established; may eventually be useful, as LTG induces its own metabolism by a factor of 25% Dosage: 75-250 mg/day (with CBZ 300-500mg/day; with VPA 50-150 mg/day). Initial dosage should be low with slow increases, as high initial dose and rapid increase is associated with higher risk of severe rash
influences the synthesis and concentration of GABA, blocking calcium channels and binding to the gabapentine receptor, related to voltage-dependent calcium channels *
!, ' *
Half-life: 5-7 hrs. The short half life suggests that split dosing may be necessary for good response, but it is not at all clear that its mood stabilizing effects depend on the presence of a significant serum level at all times. The reported cases of clinical improvement when shifting from once-a-day to split dosing may be attributable to increased absorption (see below under "Dosage"). Metabolism: none - renal excretion Maintenance therapeutic range: N/A Dosage: 300-3600 mg/day. Dosage range is variable; when given as an adjunct mood stabilizer, as little as 300 mg/day can be useful, but doses of 3600 mg/day or higher have been tried. Note: intestinal absorption is via an active transport mechanism that is saturable, so single doses of more than 900-1200 mg are incompletely absorbed. You must split the dose when getting into higher dosage ranges. (An added benefit here is that impulsive overdose on GBP is essentially impossible.) Drug interactions: none known, except a small (20%) decrease in GBP bioavailability when co-administered with Maalox Side effects: sedation, fatigue, ataxia; ejaculatory problems have been reported Cautions: sudden discontinuation in patients with OCD may cause anxiety, insomnia, increased obsessional thinking, and depression; occasional reports of paradoxical anxiety especially in brain-injured adults and developmentally delayed children Routine laboratory monitoring: none
may cause anxiety, insomnia, increased obsessional thinking, and depression; occasional reports of paradoxical anxiety especially in brain-injured adults and developmentally delayed children
Reduced estradiol plasma concentrations occur with concurrent topiramate, suggesting the need for higher doses of oral contraceptives when coadministered with topiramate
calculiThe incidence of calculi was derived from neurological studies using doses of ~400mg/day, so the incidence of stones for patients on lower doses is probably less. Since the calculi are calcium, however, those patients taking extra calcium for, eg, osteoporosis prevention may be at greater risk. In any case, the drug company pharmacist I spoke to recommends maintaining . precautionary measure as well. In selected cases at high risk for calculi where continuation of TPM is nevertheless strongly desired, one might consider adding ammonium chloride (which may give more reliable urine acidification Dosage: 100-200 mg/day, perhaps higher (for seizure disorder 400mg/day is recommended) Drug interactions: TPM is reported to decrease serum levels of CBZ, VPA, digoxin, OCPs (note: decreases ethinyl estradiol by 20% at 200mg/day, and by 30% at 800mg/day; even a 20% drop may in some cases be enough to compromise contraception), and itself, and to increase phenytoin levels; TPM levels are decreased by CBZ and phenytoin, and to a minor extent by VPA
"atypical antipsychotics." What does that mean? Some people would say his original definition was that it's a drug that has positive symptom reduction without extrapyramidal symptoms (EPS). Others would say other things, but the issue is that they don't have the EPS for every pound o In the nigrostriatal pathway, this reaction may reverse some of the D2 blockade by atypical antipsychotics through a process called disinhibition. When serotonin receptors are blocked in this pathway, dopamine levels increase. The naturally occurring dopamine is then “disinhibited” and fills D2 receptors, preventing blockade by the antipsychotic agent. With less D2 blockade in nigrostriatal pathways, motor side effects are reduced (Figure 2).
hat receptor properties can enhance the ability of an atypical to improve mood and cognition? What does the 5HT2A antagonist property have to do with that? Normally, the serotonin neuron (in yellow) talks to the dopamine and norepinephrine neurons and tells them to be quiet, to step on the brake. If you interfere with that, you don't inhibit anymore; and, if you don't inhibit anymore, you disinhibit, which is a fancy way of saying, "turning it on." So, to disinhibit means not another way to do it, but rather to turn things on. If you block the natural ability of serotonin to stop norepinephrine and dopamine release, you enable the dopamine and the norepinephrine to be released. So blocking this causes release. (Enlarge Slide)If you don't believe me and if you don't believe that this is special, put a dialysis probe into the front of a rat brain. You don't increase serotonin; you don't increase dopamine; you don't increase norepinephrine; and you don't improve cognition
olanzapine in 2000, all five atypical antipsychotics, namely risperidone (2003), quetiapine (2004), ziprasidone (2004), and aripiprazole (2004), have been approved by the FDA for the management of acute mania. Clozapine is the only atypical antipsychotic not FDA approved for any phase of bipolar disorder. This article will systematically review some of the major studies published, randomized controlled monotherapy, and adjunct therapy trials involving five atypical antipsychotics and newer anticonvulsants for the treatment of acute bipolar mania olanzapine in 2000, all five atypical antipsychotics, namely risperidone (2003), quetiapine (2004), ziprasidone (2004), and aripiprazole (2004), have been approved by the FDA for the management of acute mania. Clozapine is the only atypical antipsychotic not FDA approved for any phase of bipolar disorder. This article will systematically review some of the major studies published, randomized controlled monotherapy, and adjunct therapy trials involving five atypical antipsychotics and newer anticonvulsants for the treatment of acute bipolar mania
Asenapine (Saphris) Asenapine belongs to the dibenzo-oxepino pyrrole class of atypical antipsychotic agents. It was approved by the FDA in August 2009 for the treatment of schizophrenia in adults and as acute therapy (either as monotherapy or adjunctive therapy) for manic or mixed episodes associated with bipolar I dis - order.29 Asenapine is a high-affinity antagonist at 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT5–7 serotonergic receptors; at D1- to D4-dopaminergic receptors; at alpha1- and alpha2-adrenergic receptors; and at H1-histaminergic receptors. 29 It demonstrates moderate antagonist affinity for histamine H2 receptors and no appreciable affinity for muscarinic cholinergic receptors. Asenapine is not recommended for patients with severe hepatic impairment; however, no dosage adjustments are required based on the degree of renal impairment.29 Although no contraindications are listed in the prescribing information, a boxed warning mentions an increased mortality rate in older patients with dementia-related psychosis
useful adjuncts with mood stabilizers in the treatment of acute mania effective in place of or in conjunction with a neuroleptic in sedating the acutely agitated manic patient while waiting for the effects of other primary mood-stabilizing agents to become evident . Lorazepam- multiple routes of administration and favourable intramuscular absorption, become a useful choice. lorazepam and clonazepam are preferable to neuroleptics if the possibility of precipitating extrapyramidal symptoms and acute dystonias is unacceptable. disadvantage- dependence ,dysphoria clonazepam and lorazepam promote sleep improvement. These drugs have a high therapeutical rate and although inducing somnolence, dizziness and ataxia, their safety profile is favorable when compared to extrapyramidal reactions or tardive diskinesia seen with antipsychotics clonazepam is efficient and safe in the treatment of acute mania and that the results with lorazepam clonazepam could reduce the frequency of cycles, and some disadvantage are their propensity for dependence and, in patients with comorbid substance use disorder, the potential to induce another substance use disorder is a cause for concern. Benzodiazepines also have the potential to cause either dysphoria or disinhibition in some patientsBenzodiazepines clonazepam and lorazepam promote sleep improvement. These drugs have a high therapeutical rate and although inducing somnolence, dizziness and ataxia, their safety profile is favorable when compared to extrapyramidal reactions or tardive diskinesia seen with antipsychotics, to which bipolar patients are at higher risk.59 Despite the methodological limitations found60 in metanalyses about the use of clonazepam and lorazepam in acute mania, it was concluded that clonazepam is efficient and safe in the treatment of acute mania and that the results with lorazepam remain uncertain. With regard to the prophylactic treatment the results were controversial.61 As an adjunctive medication, clonazepam could reduce the frequency of cycles, and some patients taking neuroleptics plus lithium can benefit from the replacement by clonazepam plus lithium, although there is no consensus regarding the lower relapse risk during the replacement.62 clonazepam and lorazepam promote sleep improvement. These drugs have a high therapeutical rate and although inducing somnolence, dizziness and ataxia, their safety profile is favorable when compared to extrapyramidal reactions or tardive diskinesia seen with antipsychotics, to which bipolar patients are at higher risk.59 Despite the methodological limitations found60 in metanalyses about the use of clonazepam and lorazepam in acute mania, it was concluded that clonazepam is efficient and safe in the treatment of acute mania and that the results with lorazepam remain uncertain. With regard to the prophylactic treatment the results were controversial.61 As an adjunctive medication, clonazepam could reduce the frequency of cycles, and some patients taking neuroleptics plus lithium can benefit from the replacement by clonazepam plus lithium, although there is no consensus regarding the lower relapse risk during the replacement.62
Treating bipolar disorders because of its anticonvulsant properties high lipid solubility, and good penetration into the CNS
. Children and adolescents have higher volumes of body water and higher GFR than adults. The resulting shorter t1/2 of Li+ demands dosing increases on a mg/kg basis, and multiple daily dosing is often required. A limited number of controlled studies suggest that valproate has efficacy comparable to that of Li+ for mania in children or adolescents (Danielyan and Kowatch, 2005). As with Li+, weight gain and tremor can be problematic; moreover, there are reports of hyperammonemia in children with urea-cycle disorders. Ongoing monitoring of platelets and liver function tests, in addition to serum drug levels, is recommended. There have been no controlled studies of carbamazepine for the treatment of children and adolescents with mania, although there is substantial safety data for epilepsy indications in this age group GERIATRIC: VALPROATE ALTERNATIVE parkinsonism and tardive dyskinesia from D2 antagonism, confusion from antipsychotic medications with antimuscarinic properties, and ataxia or sedation from Li+ or anticonvulsants.
for women taking lithium in early pregnancy in addition to the regular 18 week morphological scanning
The NMDA receptor is activated by glutamate, a co-agonist (either glycine or D-serine) and depolarization, to open and permit the entry of Na+ and Ca2+ (Fig. 2). The NMDA receptor channel is composed of combination of NR1, NR2A, NR2B, NR2C, NR2D, NR3A and NR3B subunits (Fig. 2). It is generally believed that activation of the AMPA receptor results in neuronal depolarization sufficient to liberate the Mg2+ cation from the NMDA receptor, thereby permitting its activation. NMDA receptors play a crucial role in regulating synaptic plasticity (Malenka and Nicoll, 1999), including AMPA receptor trafficking. The best-studied forms of synaptic plasticity in the CNS are long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission. The molecular mechanisms of LTP and LTD are characterized extensively and proposed to represent cellular models of learning and memory (Malenka and Nicoll, 1999). During NMDA-receptor-dependent synaptic plasticity, Ca2+ influx through NMDA receptors can activate a wide variety of kinases and/or phosphatases that, in turn, modulate synaptic strength (Fig. 2). Recent data indicate that AMPA receptor trafficking, including receptor insertion, internalization and delivery to synaptic sites provides an elegant mechanism for activitydependent regulation of synaptic strength. AMPA receptor subunits undergo constitutive endocytosis and exocytosis; however, the process is highly regulated and several signal transduction cascades can produce short- and long-term changes in expression of AMPA receptor subunits at the synaptic surface (Malenka and Nicoll, 1999). Although the mechanisms of LTP and LTD have not been elucidated completely, it is widely accepted that AMPAreceptor trafficking is the key player in these phenomena GLU GLU GLU GKU
Combined tamoxifen/lithium therapy was superior to lithium alone for rapidly reducing manic symptoms; results were apparent as early as day 7. In that study, all psychotropic medications except benzodiazepines were discontinued at least 48 hours before randomization Three controlled trials have associated tamoxifen as monotherapy or as augmentation with improved scores on the Young Mania Rating Scale (YMRS).
Glycine is a co-transmitter at glutamate receptors whose synaptic action is terminated by presynaptic reuptake transporters. There are two human forms of the glycine reuptake pump: GlyT1, which is localized to cortical areas; and GlyT2, which is concentrated in spinal cord.
is still open to debate
PHARMACOTHERAPY OF MANIA
PHARMACOTHERAPY OF MANIA
As we go along….
Introduction to mood disorders
DSM 4 criteria & subtypes
Pharmacology of antimanic drugs
Non pharmacological treatments
Treatment in special populations
Treatment of resistant mania
400 B.C- Hippocrates
30 A.D- Roman physician described melancholiaAretaeus of Cappadocia
1949, John Cade
Works of Sigmund Freud
Mania & Hypomania
– Distinct period of an abnormally and persistently elevated
expansive, or irritable mood lasting for at least 1 week, or less if a
patient must be hospitalized
– At least 4 days
– Not sufficiently severe to cause impairment in social or
occupational functioning, and
– No psychotic features are present
Cyclothymia - one or more
Striatum, the nucleus accumbens,
VTA , hypothalamus,
funtion - D₂
D₁ and D₂
Cholinergic monoaminergic interaction hypothesis
Complex interrelations of cholinergic and monoaminergic neurotransmitter
Play a role in the pathophysiology and treatment of affective disorders.
Hypocholinergic or hyperadrenergic drive would cause mania.
By stimulation of muscarinic M4 receptors
M4 receptors are found in high density in limbic and cortical, decrease
precursors, such as lecithin (phosphotidyl
choline) or choline in combination with lithium, have
been used to successfully treat manic patients.
• Major excitatory neurotransmitters in the CNS.
• Intergral for synaptic transmission in brain circuitry.
• Key regulator of synaptic strength and plasticity
• Bind to (NMDA) receptor, and an excess of
• High concentration of NMDA receptors exists in the
Increase in Gs levels in frontal, temporal and occipital
cortices of BD subjects.
Mononuclear leucocytes of manic patients
increase in the activity
of basal and activated
AC among maniac
increase in PIP2
The PKC signaling pathway
• Regulation of neuronal excitability
• neurotransmitter release
• long-term synaptic events
attenuation of PKC activity may play a
role in the antimanic effects of mood stabilisers
Modulation of proteins
Abnormal Ca2+ homeostasis in bipolar disorder
Elevated intracellular Ca2+ levels in platelets, lymphocytes and
neutrophils of patients with BD
Marked blunting of Gproteinactivated PI hydrolysis
Altered mRNA expression of
proteins important roles in Ca2+
Introduction of Li+ in 1949
(Li+) is the lightest of the alkali metals
Monoamines implicated in the pathophysiology of
Second-messenger and other intracellular
molecular mechanisms involved in signal
Gene regulation and cell survival.
Lithium increase the
SE inhibitory input to
VTA and SNc nuclei
Lithium at conc of 1-10
mEq/L inhibits the Ca++dependent release of NE
Influence G-protein function is by modulating the
modification of ADP-ribosylation of Gproteins
Interference with PIP2
Completely absorbed in GIT within 6–8 hours; peak plasma levels in
30 minutes to 2 hours
Distribution: Initial volume of distribution is 0.5 L/kg, rising to 0.7–
0.9 L/kg; some sequestration in bone. No protein binding.
Excretion: virtually entirely in urine. Lithium clearance about 20% of
creatinine. Plasma half-life about 20 hours
Target plasma concentration: 0.6–1.4 mEq/L
Dosage: 0.5 mEq/kg/d in divided doses
Carbonate capsules slow release tablets citrate syrup (8 mmol/
• Acceptably safe are between 0.6 and 1.5 mEq/L.
1.0-1.5 mEq/L- acutely manic or hypomanic patients.
0.6-1.0 mEq/L long-term prophylaxis.
• 0.8-1.0 mEq/L experience decreased relapse risk
• Trough from samples obtained 10-12 hours after the last
oral dose of the day.
serum levels is often
necessary to obtain a
•Acute poisoning - Voluntary or
accidental ingestion in a previously
•Acute-on-chronic - Voluntary or
accidental ingestion in a patient currently
•Chronic or therapeutic poisoning Progressive lithium toxicity, generally in a
patient on lithium therapy
Acute Toxicity and Overdose
Nausea, vomiting, abdominal pain, profuse diarrhea
Ataxia, coma, and convulsions
Mental confusion, hyperreflexia, gross tremor, dysarthria, seizures,
and cranial nerve and focal neurological signs
Coma and death.
Cognitive and motor neurological damage irreversible, with
persistent cerebellar tremor being the most common
Role of sodium
•Admit patients with serum lithium levels higher
than 2 mEq/L.
•Admit to an ICU patients with chronically elevated
lithium levels higher than 4 mEq/L
Polyuria and compensatory polydipsia
Benign, diffuse, non tender thyroditis
Benign and reversible T-wave flattening in ~20% of
patients , U wave enlargement
Sinus bradycardia, AV blocks
Dermatitis, folliculitis, and vasculitis can occur with
Floppy baby syndrome
Iminostilbene derivative with a tricyclic structure
• Mechanism of action
Inositol depletion as a
stabilizing properties (Williams
et al., 2002).
• Absorbed slowly and erratically after oral administration
• 75% to 90% is protein bound
• Undergoes extensive hepatic metabolism predominantly by conversion to a
• Substrate and inducer of CYP3A4
• Induces CYP2C, CYP3A, and UGT, thus enhancing the metabolism of drugs
degraded by these enzymes
• Half life – 20 to 40hrs
• Therapeutic plasma concentrations 6 to 12 µg/mL
• Acute bipolar mania- 400-1400mg/day
• Maintenance therapy- 4-12 ug/ml drawn at 12
hrs after last dose, minimum of 5 days after last
Generalized tonic-clonic seizures
• Absence seizures
• Trigeminal neuralgia.
400 mg/day- larger dose given at bedtime due to the
Titration proceeds by 200-mg increments every 24-48
hours based on clinical response and serum trough
Extended-release form – FDA 2005
Better tolerated compared to older preparations
Effective as monotherapy with once-daily dosing
Immediate release forms of
carbamazepine cannot be loaded
Nausea, vomiting, diarrhoea and visual
Hypersensitivity – rash, photosensitivity,
hepatitis, granulocyte suppression and
ADH action enhancement – hyponatremia
and water retention
Transient elevation of hepatic differential,reticulocyte
Aplastic anemia,AgranulocytosisSGPT every 3 months
10-keto analogue of carbamazepine.
Metabolite: MHD- 10-monohydroxy derivative
Half-life 8-10 h
Therapeutic use: 600 -1200 mg/day.Augmented to 1400 to
2400 mg/day in order to obtain the desired effect
DRUG INTERACTION: reduces the plasmatic levels of
Substitution of oxcarbazepine for
carbamazepine is associated with
increased levels of phenytoin and
Mechanism of action
Inhibit the activity of glycogen synthase kinase-3 –ALTER
INHIBIT MYO-INOSITOL PHOSPHATASE
Reduction in arachidonic acid turnover in brain membrane
Interact with nuclear regulatory factors that affect gene
expression AP-1, AMI-1, PEBP-2
Increase expression of Bcl-2, which is associated with
protection against neuronal degeneration/apoptosis
Reduce isofoms of PKC
Completely absorbed after oral administration t ½ : 14 hours
plasma proteins bound ~90%
Metabolism: beta-oxidation and UGT enzymes
VA Glucuronide (40% of VA) Urinary excretion
3 oxo VA
(33% of VA) Urinary excretion
2 ene VA
Delayed but significant accumulation in brain
< 5% excreted unchanged in urine
Increases the serum levels of SVP
Phenytoin Phenobarbitone : 70%
: > 2.5 times of T ½
CBZ Metabolite increased
Rufinamide, Lorazepam, Felbamate,
TCAs, Zidovudine, Nimodipine
DRUGS ↓ Serum SVP
CBZ + DPH (Combined)
↓ SVP by
(Reduction is more in children)
↓ SVP by
Meropenem, Imepenam, Rifampicin,
• Acute mania
Oral loading of VPA can achieve rapid control of symptoms- 3 days
Day 1: single dose of 20 mg/kg
Days 2-4 :same dose but split bid
Day 4 : labs (VPA level, platelets, LFTs) then titrate dose to get level > 80
ug/ml or best clinical response.
Some patients need > 100ug/ml.
Effective at surprisingly low doses,125-500 mg/day.
Maintenanace: Superior to lithium in preventing recurrence of episode.
Immediate Release-12-hour troughs are used to guide treatment
Extended Release- 24-hour trough levels
• Weight gain,GI distress
• Tremor, Ataxia
• Dizziness, sedation, headache, nausea, dyspepsia
Hair loss- curly scalp hair .
• Severe hepatic damage can occur within the first six months of
• LFT TO BE MONITERED- fulminanat hepatits!!!!
Acute pancreatitis,PCOD –RARE
Half-life -25-35 hrs
Metabolized primarily by glucuro nidation to an inactive
the t1/2 and plasma
Protein binding ~55%
The kinetics linear at steady-state within a dose range of
100 to 700 mg/day
chewable dispersable formulations
• Maintenance therapeutic range: not established
75-250 mg/day (with CBZ 300-500mg/day; with VPA 50-150 mg/day
LTG monotherapy: 25 mg/day week 1
50 mg/day week 2
up to target dose of 150-200 mg/day
In combination with VPA
In combination with CBZ
12.5 mg/day week 1
25 mg/day week 2
target dose of 75-100mg/day
50 mg/day wks 1-2
100 mg/day weeks 3-4wks
target dose of 300 mg/day
Fixed lithium dose (800 mg/day)
Treatment-resistant depression- 100 mg/day to 20 mg/day of
• Bipolar I depression- 200mg/day (Maintenanace)
• Rapid cycling- 100 to 500 mg per day.
Dizziness, ataxia, blurred or double vision, nausea, vomiting
Stevens-Johnson syndrome and DIC
• Consist of a GABA molecule covalently bound to a lipophilic
cyclohexane ring or isobutane.
Centrally active GABA agonist,
High lipid solubility
• Transfer across the blood-brain barrier.
• Blocking of voltage-dependent calcium channels
Its use in bipolar disorder is based on clinical
impressions of efficacy, usually as an adjunctive
agent; it has not at this point been adequately
established as a primary mood stabilizer!!!!
Orally absorbed.Half-life: 5-7 hrs.
• Metabolism: none
split dosing may
be necessary for
• Excreted unchanged in urine
• Maintenance therapeutic range: N/A
• Dosage: 300-3600 mg/day. Dosage range is variable; when
given as an adjunct mood stabilizer
• “You must split the dose when getting into higher dosage
• Drug interactions: none
• Fatigue, ataxia
• Ejaculatory problems
sudden discontinuation in patients with OCD
Rapidly absorbed after oral administration
(10-20%) binding to plasma proteins
Mainly excreted unchanged in the urine.
Metabolism by hydroxylation, hydrolysis, and
glucuronidation with no single metabolite
t1/2 is ~24 hrs
Further double-blind studies to elucidate the antimanic
and mood stabilizing effects of topiramate are warranted.
Lorazepam and Clonazepam
Mild to moderate manic or
Cannot tolerate lithium
Useful adjuncts with mood stabilizers in the treatment of acute
• Lorazepam- 2 to 4 mg per day, three to four divided doses.
Titrated up to a target dose ranging from 3 to 8 mg per day
• Clonazepam 1 - 3 mg per day, two divided doses.
• 2 to 6 mg per day, depending upon efficacy and tolerabity
• high as 24 mg per day
• Promote sleep improvement
Sedation, and respiratory depression
Calcium channel blockers
Nimodipine may be more effective than
• Special promise for rapid and ultrarapid cycling patients
Verapamil and nimodipine
• Controlled symptoms of mania in PREGNANCY
• VERAPRAMIL- 160-320mg/day
• Low teratogenecity
• ONLY Li+ has FDA approval for child/adolescent bipolar
disorder for ages 12 years.
30 mg/kg/day given in three
divided doses will produce a Li+
concentration of 0.6-1.2 mEq/L in
Aripiprazole and risperidone 10-17yrs
Targeting lower maintenance serum levels (0.6-0.8 mEq/L)
may reduce the risk of toxicity.
As GFR> 60 mL/min - alternative agents, despite lithium's
• Use of loop diuretics and angiotensin-converting enzyme
Lithium- Category D
• First trimester - Ebstein’s Anomaly
• 1: 10-20,000 to 1: 1000. foetal echo is warranted, Floppy
• Maternal polyuria
Valproate: Category D
Neural tube defects, limb defects, cardiac defects and
Lamotrigine & Carbamazepine: Category D
Absolute risk of birth defects (~ 5-6%). n oral cleft
Atypical Antipsychotic Medications
Weight gain throughout the pregnancy
• Risk of gestational diabetes.
Novel stratergies and novel therapies
• Decreasing the episode severity
• Increasing the inter-episode interva
Non-competitive, high-affinity NMDA receptor antagonist
Demonstrated potential to relieve “manic-like” symptoms in
animal models; appeared beneficial in two open-label studies
Hypothesized to be involved in the pathophysiology of mania.
An adjunct to mood stabilizer or antipsychotic
Protein kinase C (PKC) inhibitor
• Antiestrogenic drug
. The Canada Network for Mood and
Anxiety Treatment (CANMAT) lists it as a
• Crosses the blood-brain barrier and is relatively well
tolerated (up to 200 mg/d)
• starting dosage 20 mg twice daily (40 mg/d).
Subsequently increased by 10 mg to achieve 80 mg/d in
twice-daily divided doses.
• long-term safety data are limited
• increased risk of endometrial carcinoma and uterine
Young Mania Rating
The GlyT1 inhibitor SSR504734
Effective as haloperidol in blocking PCP-induced CNS
metabolic changes in rats.
Lurasidone - 5-HT/DA antagonist- FDA approval 2009
Possesses potent activity at 5-HT7 receptor sites, actions
that, based on preclinical and early clinical studies, may be
associated with cognitive benefits
Xanomeline, M1/M4 agonist, has shown antipsychotic and
procognitive affects .schezo trial
• transcranial magnetic stimulation
• transcranial direct current stimulation
• Deep brain stimulation (DBS) that targets brain areas via
• Stimulation could elicit circuit-level modifications that can
• A prolonged or severe episode of mania
• Severe depressive illness or refractory
• Should stop once a response is achieved or if the
patient develops side-effects.