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PHARMACOTHERAPY OF MANIA

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Detail explanation of mechanism of action of Lithium as a mood stabiliser

Detail explanation of mechanism of action of Lithium as a mood stabiliser


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  • 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.[101] Neuroimaging was first utilized as a tool for psychiatry in the 1980s.[102] The discovery of chlorpromazine's effectiveness in treating schizophrenia in 1952 revolutionized treatment of the disease,[103] as did lithium carbonate's ability to stabilize mood highs and lows in bipolar disorder in 1948.[104] Psychotherapy was still utilized, but as a treatment for psychosocial issues.[105] 
    Following Sigmund Freud's death, ideas stemming from psychoanalytic theory also began to take root.[100] 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,[6] hence the name, which means 'black bile', from Ancient Greek μέλας (melas), "dark, black",[7] + χολή (kholé), "bile";[8] 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.[9] 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
    [28]. Altered glutamate levels in plasma, serum and
    cerebrospinal fluid have been observed in human studies of
    individuals with mood disorders [29]. 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 G􀁟s 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 G􀁟s 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 G􀁟s 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 [130]. 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
  • FIRST MECHANISM
  • 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
  • Transcript

    • 1. PHARMACOTHERAPY OF MANIA Dr.Rachana Menon
    • 2. As we go along….  History  Introduction to mood disorders  DSM 4 criteria & subtypes  Pathogenesis  Pharmacology of antimanic drugs  Newer approaches  Non pharmacological treatments  Treatment in special populations  Treatment of resistant mania
    • 3.  400 B.C- Hippocrates  30 A.D- Roman physician described melancholiaAretaeus of Cappadocia  1899-Emil Kraepelin  1949, John Cade  Works of Sigmund Freud
    • 4. 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 Hypomanic episode – 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 Hypomanic episodes Dysthymic (chronic depression) episodes
    • 5. DSM-IV DIAGNOSIS OF MANIA DSM-IV
    • 6. Dopamine Hypothesis Striatum, the nucleus accumbens, olfactorytubercle. Substantia nigra, VTA , hypothalamus, cortical areas
    • 7. Mesolimbicmesocortical: Control behavior, cognitive funtion - D₂ Receptor. Nigrostriatal: Control Voluntary Movement D₁ and D₂ receptor. Tuberoinfundibular: Control prolactin secretion D₂ receptor. Vesicular monoamine transporter protein (VMAT2)
    • 8. CHOLINERGIC SYSTEM 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 cAMP Acetylcholine precursors, such as lecithin (phosphotidyl choline) or choline in combination with lithium, have been used to successfully treat manic patients.
    • 9. Noradrenergic system MHPG NE
    • 10. GLUTAMATE HYPOTHESIS • 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 glutamatergic stimulation • High concentration of NMDA receptors exists in the hippocampus
    • 11. Deleterious glutamate signaling
    • 12. Second Messengers and Intracellular Cascades  Increase in Gs levels in frontal, temporal and occipital cortices of BD subjects.  Mononuclear leucocytes of manic patients  Platelets G PROTIENS Mood states
    • 13. A significant increase in the activity of basal and activated AC among maniac subjects Significant increase in PIP2 levels
    • 14. Alter the conformation of the cytoskeleton through actin filaments. 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
    • 15. ` Modulation of proteins associated with cytoskeleton microtubules- tau, MAP-1B MAP-2, Apoptosis NEURONAL SURVIVAL destabilization of microtubules conformation
    • 16. CALCIUM-SIGNALING ABNORMALITIES  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 IMPase type2a, proteins important roles in Ca2+ TRPM2 homeostasis
    • 17. ALTERATIONS OF HORMONAL REGULATIONS
    • 18. Genetics… Strongly genetic • • • • • MZ concordance – 40 -45% Heritability – 80 – 85% Leading linked regions – 6q, 8q, 13q, 22q Leading candidate genes – BDNF – DAOA – DISC – TPH2 – SLC6A$ Genes implicated by GWAS – DGKH – CACNA1C – ANK3 Concordance in MZ twins of 50-70% Early-onset bipolar disorder may be even more genetic
    • 19. DRUG INDUCED MANIA • • • • • • • • • • • Levodopa Corticosteroids Tricyclic and monoamine oxidase inhibitor Thyroxine Isoniazid Sympathomimetic drugs Chloroquine, baclofen Alprazolam Captopril Amphetamine Phencyclidine.
    • 20. CLASSIFICATION Mood Stabiliser Anti epileptics Anti Psychotics Anti Adrenergic Drugs Lithium Sodium valporate Olanzapine Clonidine Carbamezapine Quatepine Propranalol Lamotrigine Apriprazole Gabapentin Zisaperidone Toperamate Risperidone Benzodiazepines Cholinomimetics Clonazepam Lorazepam Physostigmine Calcium Channel Blockers Verapramil Nifedipine Nimodipine
    • 21. LITHIUM  Introduction of Li+ in 1949  (Li+) is the lightest of the alkali metals  Monoamines implicated in the pathophysiology of mood disorders  Second-messenger and other intracellular molecular mechanisms involved in signal transduction  Gene regulation and cell survival.
    • 22. Lithium increase the SE inhibitory input to VTA and SNc nuclei
    • 23. AFTER Lithium at conc of 1-10 mEq/L inhibits the Ca++dependent release of NE and DA BEFORE
    • 24. Influence G-protein function is by modulating the posttranslational modification of ADP-ribosylation of Gproteins
    • 25. Interference with PIP2 PATHWAY Activated PLC INOSITOL MONOPHOSPHATE
    • 26. AXONAL GROWTH HIPPOCAMPUS
    • 27. Enhances the binding of tau to microtubules which promotes microtubule assembly DEPHOSPHORYLATION
    • 28. Decrease gene expression of PLA2
    • 29. Bcl-2 AP-1, AMI-1, PEBP-2
    • 30. PHARMACOKINETICS 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/ 5 mL)
    • 31. Thaizides Spironolactone Amiloride Furosemide Indomethacin Ibuprofen Naproxen COX-2 inhibitors Fosinopril Lisinopril
    • 32. SERUM LEVEL MONITORING • 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. • Trough concentration:0.8-1mEq/l Individualization of serum levels is often necessary to obtain a favorable risk-benefit relationship
    • 33. •Acute poisoning - Voluntary or accidental ingestion in a previously untreated patient •Acute-on-chronic - Voluntary or accidental ingestion in a patient currently using lithium •Chronic or therapeutic poisoning Progressive lithium toxicity, generally in a patient on lithium therapy
    • 34. Acute Toxicity and Overdose • Nausea, vomiting, abdominal pain, profuse diarrhea • Polyuria,Coarse tremor • 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
    • 35. SERUM PLASMA LEVELS Mmol/L Effects 0.5 None 1 Mild tremor 1.5 Coarse tremor 2 Hyperreflexia, dysarthria 2.5 Myoclonia, ataxia, confusion > 3.0 Delirium, coma, seizures
    • 36. LITHIUM TOXICITY
    • 37. Role of sodium polystyrene sulfonate (Kayexalate) NO ANTIDOTE HEMODIALYSIS •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
    • 38. Adverse effects  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 Li+ administration  Ebstein's malformation  Floppy baby syndrome
    • 39. Therapeutic uses  Acute mania- 600-mg loading dose (150,300,600mg)  Prophylactic treatment of bipolar disease  Treatment-resistant major depression  Monotherapy for unipolar depression  Suicide reduction extends to unipolar mood disorder Alzheimer type, stroke, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy,
    • 40. ANTIEPILEPTICS      CARBAMEZAPINE SODIUM VALPROATE LAMOTRIGINE TOPIRAMATE GABAPENTIN
    • 41. CARBAMAZEPINE • Iminostilbene derivative with a tricyclic structure • Mechanism of action Inositol depletion as a mechanism underlying carbamazepine's mood stabilizing properties (Williams et al., 2002).
    • 42. Pharmacokinetics • Absorbed slowly and erratically after oral administration • 75% to 90% is protein bound • Undergoes extensive hepatic metabolism predominantly by conversion to a 10,11-epoxide • 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 Anticonvulsants ,Hormonal contraceptives Neuroleptics Erythromycin,Cimetidine, Isoniazid,Fluoxetine • Therapeutic plasma concentrations 6 to 12 µg/mL
    • 43. Therapeutic uses • 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 dose change • Partial seizures • Generalized tonic-clonic seizures • Absence seizures • Trigeminal neuralgia.
    • 44. Acute mania  400 mg/day- larger dose given at bedtime due to the sedating properties  Titration proceeds by 200-mg increments every 24-48 hours based on clinical response and serum trough levels  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
    • 45. Adverse effects  Nausea, vomiting, diarrhoea and visual disturbances  Hypersensitivity – rash, photosensitivity, hepatitis, granulocyte suppression and aplastic anemia Lyell’s syndrome,Stevens-Johnson  ADH action enhancement – hyponatremia and water retention CBZ level,  Teratogenicity CBC +  Transient elevation of hepatic differential,reticulocyte transaminases count  Aplastic anemia,AgranulocytosisSGPT every 3 months till stable.
    • 46. Oxcarbazepine  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 felodipine, verapamil,OCPS Substitution of oxcarbazepine for carbamazepine is associated with increased levels of phenytoin and valproic acid
    • 47. Sodium valproate • Simple branched-chain carboxylic acid
    • 48. Mechanism of action 6 MECHANISMS IN COMMON!  Inhibit the activity of glycogen synthase kinase-3 –ALTER MARCK protiens  INHIBIT MYO-INOSITOL PHOSPHATASE  Reduction in arachidonic acid turnover in brain membrane phospholipids  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
    • 49. PHARMACOKINETICS Completely absorbed after oral administration t ½ : 14 hours plasma proteins bound ~90% Metabolism: beta-oxidation and UGT enzymes CYP2C9 CYP2C19 Metabolites: 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
    • 50. Increases the serum levels of SVP  Phenytoin Phenobarbitone : 70% Lamotrigine : > 2.5 times of T ½ CBZ Metabolite increased DPH Others: Rufinamide, Lorazepam, Felbamate, TCAs, Zidovudine, Nimodipine
    • 51. DRUGS  ↓ Serum SVP CBZ + DPH (Combined)  ↓ SVP by 50% (Reduction is more in children) Lamotrigine  ↓ SVP by 25% Estrogen (OCP)  ↓ SVP Others  ↓ SVP Meropenem, Imepenam, Rifampicin, Ritonavir
    • 52. Therapeutic uses • 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 Divalproex sodium ug/ml or best clinical response. • Some patients need > 100ug/ml. Cyclothymia:DOC 90-120 g/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
    • 53. SIDE EFFECTS • 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 treatment • LFT TO BE MONITERED- fulminanat hepatits!!!! • Acute pancreatitis,PCOD –RARE
    • 54. LAMOTROGINE • A phenyltriazine derivative
    • 55. PHARMACOKINETICS  Half-life -25-35 hrs  Metabolized primarily by glucuro nidation to an inactive 2-N-glucuronide conjugate. Phenytoin, CBZ, phenobarbital reduces the t1/2 and plasma concentrations of lamotrigine  Renal excretion  Protein binding ~55%  The kinetics linear at steady-state within a dose range of 100 to 700 mg/day  chewable dispersable formulations
    • 56. THERPEUTIC USES • 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
    • 57. Fixed lithium dose (800 mg/day) 50-100 mg/day Treatment-resistant depression- 100 mg/day to 20 mg/day of fluoxetine • Bipolar I depression- 200mg/day (Maintenanace) • Rapid cycling- 100 to 500 mg per day. Adverse effects Dizziness, ataxia, blurred or double vision, nausea, vomiting Stevens-Johnson syndrome and DIC
    • 58. GABAPENTINE • 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!!!!
    • 59. Pharmacokinetics • Orally absorbed.Half-life: 5-7 hrs. • Metabolism: none split dosing may be necessary for good response • 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 ranges.” • Drug interactions: none
    • 60. Adverse Effects • Sedation • Fatigue, ataxia • Ejaculatory problems • Caution!!!!:  sudden discontinuation in patients with OCD
    • 61. Topiramate Sulfamate-substituted monosaccharide  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.
    • 62. Adverse Effects • Sedation, dizziness, anxiety, tremor, confusion • tingling in fingers, toes • GI distress, Decrease serum levels of • Cognitive impairment, CBZ, VPA, digoxin, OCPs • Weight loss!!! • Teratogenicity, • Renal calculi!!!! 400mg/day • Therapeutic use • Acute mania 100-200 mg/day, perhaps higher (for seizure disorder 400mg/day is recommended)
    • 63. ANTIPSYCHOTICS
    • 64. Tyrosine Tyrosine Dopamine Synapse L-DOPA DA D2 Dopamine receptor
    • 65. Fills D2 receptors, preventing blockade by the antipsychotic agent. HIT AND RUN!!!!
    • 66. Prophylaxis 5mg 25mg bd 10-15mg Prophylaxis 20mg bd
    • 67. 2009 5-HT1A, 5-HT1B, 5HT2A, 5HT2B, 5HT2C, and 5HT5–7 ,
    • 68. Adverse effects
    • 69. Benzodiazepines Lorazepam and Clonazepam Hypomanic Mild to moderate manic or mixed episodes Cannot tolerate lithium Useful adjuncts with mood stabilizers in the treatment of acute mania • 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
    • 70. Calcium channel blockers Nimodipine may be more effective than Verapramil • Special promise for rapid and ultrarapid cycling patients Verapamil and nimodipine • Controlled symptoms of mania in PREGNANCY • VERAPRAMIL- 160-320mg/day • Low teratogenecity
    • 71. Treatment resistant mania • • • • Clozapine + ECT Donepezil Gabapentin, topiramate, mexiletine, IV magnesium sulphate
    • 72. Pediatric Use • 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 5 days Aripiprazole and risperidone 10-17yrs Geriatric Use • 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 therapeutic advantages • Use of loop diuretics and angiotensin-converting enzyme inhibitors
    • 73. PREGNANCY Lithium- Category D • First trimester - Ebstein’s Anomaly • 1: 10-20,000 to 1: 1000. foetal echo is warranted, Floppy baby syndrome • Maternal polyuria Valproate: Category D  Neural tube defects, limb defects, cardiac defects and facial dysmorphism .
    • 74. Lamotrigine & Carbamazepine: Category D  Absolute risk of birth defects (~ 5-6%). n oral cleft defect Atypical Antipsychotic Medications Weight gain throughout the pregnancy • Risk of gestational diabetes. RISK-BENEFIT RATIO!!!
    • 75. Novel stratergies and novel therapies • Prophylaxis • Decreasing the episode severity • Increasing the inter-episode interva GOAL Glutamatergic modulators • • • • Non-competitive, high-affinity NMDA receptor antagonist Memantine Demonstrated potential to relieve “manic-like” symptoms in animal models; appeared beneficial in two open-label studies Allopurinol Hypothesized to be involved in the pathophysiology of mania. An adjunct to mood stabilizer or antipsychotic
    • 76. TAMOXIFEN • Protein kinase C (PKC) inhibitor • Antiestrogenic drug . The Canada Network for Mood and Anxiety Treatment (CANMAT) lists it as a third-line option • 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 sarcoma Young Mania Rating Scale (YMRS).
    • 77. 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
    • 78. Brain Stimulation Non-invasive method • transcranial magnetic stimulation • transcranial direct current stimulation Invasive method • Deep brain stimulation (DBS) that targets brain areas via implanted electrodes • Stimulation could elicit circuit-level modifications that can improve symptoms
    • 79. ECT • A prolonged or severe episode of mania • Severe depressive illness or refractory depression. • Catatonia. • Should stop once a response is achieved or if the patient develops side-effects.
    • 80. THANK YOU