SEARCH RESULTS FOR: Lithium

Serotonin Syndrome Pathogenesis and Clinical Findings

Serotonin Syndrome: Pathogenesis and Clinical Findings Serotonergic Agents SSR1s, SNRIs, MOAIs, TCAs, atypical antidepressants, antibiotics, mood stabilizers (valporate, lithium), opioids, antiemetic agents, triptans, weight loss agents, drugs of abuse (e.g. cocaine, amphetamines) Therapeutic drug use • Drug interactions (esp. combo of serotonergic agents) Serotonin Syndrome Variable combination of mental status changes, autonomic instability, and neuromuscular hyperactivity ranging from mild to life-threatening with an abrupt onset (within minutes to hours) after medication ingestion and most cases resolving within 24 hours of cessation of offending medication Intentional self-poisoning Excessive serotonergic activity at 5-HT receptors centrally (brainstem) and peripherally serotonin synthesis and release serotonin reuptake and metabolism IN receptor agonism and sensitivity 4, Drug-induced changes in the relative ratio of non-serotonergic neurotransmitters (e.g. increase in noradrenaline) Altered Mental Status Anxiety, confusion, agitation, hypervigilance, pressured speech, delirium, coma Autonomic Instability Shivering, diaphoresis, fever, diarrhea, tachycardia, mydriasis, hypertension Authors: Preeti Kar Reviewers: Erika Russell Usama Malik Aaron Mackie* * MD at time of publication Notes: The Hunter Serotonin Toxicity Criteria is used to make a clinical diagnosis • History of serotonergic agent taken within past 5 weeks + any of the following clinical features: • Spontaneous clonus • Inducible clonus and either agitation or diaphoresis • Ocular clonus and either agitation or diaphoresis • Tremor and hyperreflexia • Hypertonia, temperature > 38 °C, and either ocular clonus or inducible clonus Neuromuscular Hyperactivity Hyperreflexia, muscle rigidity (esp. lower extremities), myoclonus, tremor, incoordination, trismus*, opisthotonus*, ocular clonus*, seizures *Notes: • Trismus or lockjaw, is the reduced opening of the jaw • Opisthotonus is an abnormal body position where the person is usually rigid and arches their back, with their head thrown backwards • Ocular Clonus is rhythmic or equal movements of both eyes; should be distinguished from nystagmus which has a fast and slow component Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Abbreviations: • 5-HT = serotonin • SSRI = selective serotonin reuptake inhibitors • SNRI = selective noradrenaline reuptake inhibitors • MOAI = monoamine oxidase inhibitors • TCA = tricyclic antidepressants

diabetes-insipidus-pathogenesis-and-clinical-findings

Diabetes Insipidus: Pathogenesis and clinical findings Hereditary Autoimmune/ Idiopathic Auto-antibodies destroy neurons that release antidiuretic hormone (ADH) Mass Effect/ Tumor Invasion Mass pressing on hypothalamus or pituitary Electrolyte Imbalance (mechanism unclear) Hereditary Lithium (Li) (mechanism unclear) Li enters principal cells of collecting ducts via ENaCs Li inhibits GSK3β, reducing adenylyl cyclase activity ↓ cAMP- dependent phosphorylation of aquaporin-2 ↑ Serum [Ca2+] Activation of CaSR in thick ascending limb of Loop of Henle ↓ NaCl reabsorption in thick ascending limb ↓ Generation of medullary osmotic gradient ↓ Serum [K+] ↑ Degradation of aquaporin-2 channels in collecting duct ↓ Aquaporin- 2 channels transporting water across apical membrane of collecting duct Mutation of AVPR2 gene on X chromosome Antidiuretic hormone (ADH) receptor cannot reach basolateral surface of principal cells of collecting duct Mutation of aquaporin-2 gene on chromosome 12 ↓ Fusion of aquaporins with apical membrane of collecting duct Mutation of WFS1 gene on chromosome 4 (Wolfram syndrome) ↓ Processing of antidiuretic hormone (ADH) precursors and ↓ADH-releasing neurons Surgery/ Trauma Injury to hypothalamus or pituitary stalk Mutation of PCSK1 gene on chromosome 5 Deficiency in PC1/3 (encoded by PCSK1) ↓ Processing of ADH by PC1/3 Aquaporin dysfunction ↓ Kidney response to ADH, which mediates reabsorption of water down its osmotic gradient through aquaporins ↓ Production of ADH by hypothalamus or ↓ secretion from ADH-releasing neurons in posterior pituitary (depending on location of lesion) Central Diabetes Insipidus Nephrogenic Diabetes Insipidus Abbreviations: AVPR2: arginine vasopressin receptor 2 CaSR: calcium-sensing receptor ENaC: epithelial sodium channel GSK3β: glycogen synthase kinase type 3 beta PC1/3: proprotein convertase Diabetes Insipidus Decreased ability of kidneys to concentrate urine ↓ Reabsorption of water from collecting duct into vasculature Author: Oswald Chen Reviewers: Huneza Nadeem, Ran (Marissa) Zhang, Yan Yu* Sam Fineblit* * MD at time of publication Urine becomes more dilute ↓ Urine osmolality ↑ Urine output ↓ Blood volume Blood becomes more concentrated Occurs during late sleep period Nocturia Polyuria (>3 L/day) ↑ Serum osmolality Activation of hypothalamic osmoreceptors Hypernatremia (Serum [Na+] >145 mEq/L) Polydipsia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 25, 2022 on www.thecalgaryguide.com

Lithium

Lithium: Mechanism of action and side effects Bipolar (I & II) Treatment-resistant depression Accumulated Li inhibits adenylyl cyclase Suicidality Schizoaffective Disorder Li passively enters cells in kidney, thyroid, & area postrema via sodium channels Li’s small size prevents active transport out of cells ↓ cAMP ↓ PKA phosphorylation Lithium (Li) Magnesium (Mg²⁺) analog which inhibits Mg²⁺-dependent enzymes such as glycogen synthase kinase-3β (GSK-3β) & inositol monophosphatase (IMPase). This activity modulates neuroplasticity, inflammation, & mood regulation. ↓ T3/T4 synthesis & release from thyroid Authors: Rida Mahmood, Hadi Hassan Reviewers: Taryn Stokowski, Emily J. Doucette, Rohit Ghate* * MD at time of publication ↓ T3/T4 ↑ TSH ↓ Aquaporin insertion in principal cells of collecting ducts of kidneys ↓ Water reabsorption Nephrogenic diabetes insipidus** Li carbonate (an inorganic salt) irritates gastric mucosa Li stimulates chemoreceptor trigger zone Subclinical or overt hypothyroidism Li competes with Mg2+ at cofactor site of IMPase & GSK-3β Enterochromaffin cells ↑ serotonin release ↑ Gut motility & vagal afferent nerve activation Activation of vomiting center in area postrema Nausea & vomiting** ↓ GSK-3β activity throughout brain IMPase & inositol polyphosphate phosphatase (IPP) inhibition prevents hydrolysis of inositol monophosphate to free inositol within neurons Inhibited IRS & ↓ Phosphorylation of transcription factors, PI3K/Akt signaling signaling proteins, & metabolic enzymes ↓ GLUT4 translocation & ↓ glucose uptake in muscle & adipose tissue ↓ Systemic insulin sensitivity Weight gain ↓ Downstream dopamine release in mesolimbic, mesocortical, & nigrostriatal pathways ↓ Conversion of inositol into phosphatidylinositol 4,5-bisphosphate (PIP2) ↓ Pro-apoptotic signaling (Bax, p53, & caspases) ↓ neural apoptosis ↑ Neurotrophic signaling (Akt & MAPK/ERK) ↓ D2 receptor stimulation in nucleus accumbens, prefrontal cortex, & striatum Sustained cAMP Response Element- Binding Protein activity promotes gene transcription ↑ Circadian clock proteins & transcription factor (CLOCK, BMAL1, CRY1, & PER2) stabilization in suprachiasmatic nucleus ↓ PIP2 available for cleavage into second messengers inositol triphosphate (IP3) & diacylglycerol (DAG) during G Protein activation ↓ Dopaminergic inhibition of GABAergic interneurons ↓ Availability of IP3 & DAG ↓ Reward drive in nucleus accumbens ↓ Drive & arousal in prefrontal cortex Dopamine & acetylcholine imbalance in striatum ↑ Circadian rhythm stabilization Thalamocortical motor circuit instability ↑ Brain-Derived Neurotrophic Factor expression in hippocampus & prefrontal cortex Improved sleep timing & stability ↓ Impulsivity Glutamatergic signalling stabilizes (↓ release, ↑ reuptake, ↓ NMDA activity) ↓ Aggression ↑ Involuntary rhythmic muscle activity ↑ Neuronal survival, synaptogenesis, & dendritic growth ↓ Tau hyper- phosphorylation ↑ GABAergic inhibition Excitatory–inhibitory balance in cortical & limbic regions normalizes ↓ Psychomotor agitation Upper extremity postural tremor ↑ Gray matter volume & prefrontal cortex– hippocampus connectivity Neuroprotection & ↓ dementia risk Prefrontal cortex exerts better top-down control ↓ Amygdala hyper-responsivity ↑ Hippocampal regulation of thought loops Improved ↓ Irritability ↓ Mood lability decision-making ↑ Working memory ↓ Distractibility ↓ Racing thoughts Mood stabilization (↓ frequency & severity of manic & depressive episodes) ** See Corresponding Calgary Guide slides Legend: Pathophysiology Mechanism Pharmacologic Effect Side Effects Published Nov 2, 2025 on www.thecalgaryguide.com