After nearly a century of intensive research and clinical investigation, the pathophysiology of psychiatric disorders remains an enigma. Short of a clear understanding of how psychiatric symptoms are produced, the various cognitive, emotional, and behavior patterns that characterize psychiatric disorders continue to be grouped into syndromes and treated accordingly. The weakness of this approach is that the treatment is administered without a clear understanding of what pathological process is being treated. Moreover, the symptoms of most psychiatric disorders are frequently changing and melding into one another. This leads to diagnostic confusion, medication stacking, and poor treatment outcomes, all of which erode patient trust and perpetuate the stigma of mental illness. In this seminal report, a new hypothesis on the pathophysiology of psychiatric disorders will be presented based on multidisciplinary evidence that nearly all psychiatric disorders and their functional comorbidities are rooted in a single, shared, neurophysiological abnormality. The report will then trace that abnormality to its molecular roots and introduce a new paradigm through which the many faces of mental illness can be understood and uniformly treated. The Multi-Circuit Neuronal Hyperexcitability hypothesis of psychiatric disorders posits that an inherent hyperexcitability of the neurological system is at the root of mental illness and provides a precise, functionally-specific framework that eliminates diagnostic confusion, informs a unified treatment approach, and helps remove the long-held stigma of mental illness.
Michael R. Binder,
The Multi-Circuit Neuronal Hyperexcitability Hypothesis of Psychiatric Disorders, American Journal of Clinical and Experimental Medicine.
Vol. 7, No. 1,
2019, pp. 12-30.
Wang S, Tudusciuc O, Mamelak AN, et al. (2014) Neurons in the human amygdala selective for perceived emotion. PNAS. 111(30): E3110-E3119.
Wang S, Yu R, Tyszka JM, et al. (2017) The human amygdala parametrically encodes the intensity of specific facial emotions and their categorical ambiguity. Nature Communications. 8:14821.
Jimenez JC, Su K, Goldberg AR, et al. Anxiety Cells in a hippocampal-hypothalamic circuit. Neuron. 2018; 97(3):670-683.e6.
Yizhar O, Fenno LE, and Deisseroth K. (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature. 477:171-178.
Beyeler A, Namburi P, Glober GF, et al. (2016) Divergent routing of positive and negative information from the amygdala during memory retrieval. Neuron. 90:348-361.
Penfield W. (1936). Epilepsy and surgical therapy. Archives of Neurology and Psychiatry. 36(3):449-484.
Fuchs E and Flügge G. (2003) Chronic social stress: effects on limbic brain structures. Physiology & Behavior. 79(3):417-427.
Mehler B, Reimer B, Coughlin JF, and Dusek JA. (2009) Impact of Incremental Increases in Cognitive Workload on Physiological Arousal and Performance in Young Adult Drivers. Transportation Research Record: Journal of the Transportation Research Board. (2138):6-12.
Rose GM, Diamond DM, Pang K, and Dunwiddie TV. (1988) Primed Burst Potentiation: lasting synaptic plasticity invoked by physiologically patterned stimulation. In: Haas HL and Buzsàki G. (eds) Synaptic Plasticity in the Hippocampus. Springer, Berlin, Heidelberg.
Bromfield EB, Cavazos JE, Sirven JI, editors. (2006) In: An introduction to epilepsy. West Hartford (CT): American Epilepsy Society. Chapter 1: Basic Mechanisms Underlying Seizures and Epilepsy.
McKee HR and Privitera MD. (2017) Stress as a seizure precipitant: Identification, associated factors, and treatment options. Seizure. 44:21-26.
Lawn N, Lieblich S, Lee J, and Dunne J. (2014) Are seizures in the setting of sleep deprivation provoked? Epilepsy & Behavior. 33:122-125.
Coffey CE, Figiel GS, Weiner RD, and Saunders WB. (1990) Caffeine augmentation of ECT. American Journal of Psychiatry. 147(5):579-585.
Winston AP, Hardwick E, and Jaberi N. (2005) Neuropsychiatric effects of caffeine. Advances in Psychiatric Treatment. 11(6):432-439.
Vezzani A. (2005) Inflammation and epilepsy. Epilepsy Curr. 5(1):1-6.
Bowcut JC and Weiser M. (2018) Inflammation and schizophrenia. Psychiatric Annals. 48(5):237-243.
Raison CL and Miller AH. (2015) Anti-Inflammatory agents as antidepressants: Truth or Dare. Psychiatric Annals. 45(5):255-261.
Bough KJ and Rho JM. (2007) Anticonvulsant mechanisms of the Ketogenic Diet. Epilepsia. 48(1):43-58.
Bostock ECS, Kirkby KC, and Taylor BVM. (2017) The current status of the Ketogenic Diet in psychiatry. Front Psychiatry. 8(43):1-40.
Ingram J, Zhang C, Cressman JR, et al. (2014) Oxygen and seizure dynamics: I. experiments. J Neurophysiol. 112(2):205–212.
Hüfner K, Brugger H, Kuster E, et al. (2018) Isolated psychosis during exposure to very high and extreme altitude – characterization of a new medical entity. Psychological Medicine. 48(11):1872-1879.
Goddard GV. (1967) Development of epileptic seizures through brain stimulation at low intensity. Nature. 214:1020-1021.
Mazarati A, Shin D, Auvin S, Caplan R, and Sankar R. (2007) Kindling epileptogenesis in immature rats leads to persistent depressive behavior. Epilepsy Behav. 10:377–383.
Finocchi C and Ferrari M. (2011) Female reproductive steroids and neuronal excitability. Neurol Science. 32(Suppl 1):31-35.
Luoma JI, Stern CM, and Mermelstein PG. (2012) Progesterone inhibition of neuronal calcium signaling underlies aspects of progesterone-mediated neuroprotection. The Journal of Steroid Biochemistry and Molecular Biology. 131(1-2):30–6.
Stein DG. (2008) Progesterone exerts neuroprotective effects after brain injury. Brain Research Reviews. 57(2):386–97.
Devinsky O, Cilio MR, and Friedman D. (2014) Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 55(6):791-802.
Sankaranarayanan A, Wilding H, Neill E, and Castle D. (2018) A critical systematic review of evidence for cannabinoids in the treatment of schizophrenia. Psychiatric Annals. 48(5):214-213.
Zuardi A, Shirakawa I, Finkelfarb E, and Karniol I. (1982) Action of cannabidiol on the anxiety and other effects produced by delta-9-THC in normal subjects. Psychopharmacology (Berl). 76(3):245-250.
Papanicolaou J, Summers RJ, Vajda FJ, and Louis WJ. (1982) Anticonvulsant effects of clonidine mediated through central alpha2-adrenoceptors. Eur J Pharmacol. 77(2-3):163-166.
Kontaxakis V, Markianos M, Markidis M, and Stefanis C. (1989) Clonidine in the treatment of mixed bipolar disorder. Acta Psychiatrica Scandinavica. 79(1):108-110.
Farook JM, Krazem A, and Barron S. (2008) Acamprosate attenuates the handling induced convulsions during alcohol withdrawal in Swiss Webster mice. Physiol Behav. 95(1-2):267-279.
Mason BJ and Heyser CJ. (2010) Acamprosate: a prototypic neuromodulator in the treatment of alcohol dependence. CNS Neurol Disord Drug Targets. 9(1):23-32.
Maremmani AGI, Bacciardi, S, and Maremmani I. (2014) Six-month outcome in bipolar spectrum alcoholics treated with acamprosate after detoxification: a retrospective study. Int J Environ Res Public Health. 11(12):12983-12996.
Hertzman M, Patt IS, and Spielman LA. (2009) Open-label trial of acamprosate as a treatment for anxiety. Prim Care Companion J Clin Psychiatry. 11(5):267.
Schwartz TL, Siddiqui UA, Raza S, and Costello A. (2010) Acamprosate calcium as augmentation therapy for anxiety disorders. Annals of Pharmacotherapy. 44(12):1930-1932.
Borowicz KK, Sêkowski A, Drelewska E, and Czuczwar SJ. (2004) Riluzole enhances the antiseizure action of conventional antiepileptic drugs against pentetrazole-induced convulsions in mice. Pol J Pharmacol. 56:187-193.
Zarate C. (2008) Riluzole in psychiatry: a systematic review of the literature. Expert Opin Drug Metab Toxicol. 4(9):1223-1234.
Deepmala, Slattery J, Kumar N, et al. (2015) Clinical trials of N-acetylcysteine in psychiatry and neurology: A systematic review. Neuroscience and Biobehavioral Reviews. 55:294-321.
Standley CA, Irtenkauf SM, and Cotton DB. (1995). Anticonvulsant effects of magnesium sulfate in hippocampal-kindled rats. Journal of Biomedical Science. 2(1):57-62.
Eby GA and Eby KL. (2006) Rapid recovery from major depression using magnesium treatment. Medical Hypotheses. 67(2):362-370.
El Idrissi A, Messing J, Scalia J, and Trenkner E. (2003) Prevention of epileptic seizures by taurine. Advances in Experimental Medicine and Biology. 526:515–25.
Kong WX, Chen SW, Li YL, et al. (2006) Effects of taurine on rat behaviors in three anxiety models. Pharmacol Biochem Behav. 83(2):271–276.
Lundberg L. (2011) A modeling study of effects of polyunsaturated fatty acids on neuronal excitability: implications in epilepsy. Master ́s Thesis in Computer Science at Stockholm University, Sweden.
Peet M and Stokes C. (2005) Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs. 65(8):1051-1059.
Lian X-Y, Zhang Z, and Stringer JL. (2006) Anticonvulsant and neuroprotective effects of ginsenosides in rats. Epilepsy Res. 70(2-3):244-56.
Stringer JL. (2009) Ginseng and other herbal treatments for epilepsy. Encyclopedia of Basic Epilepsy Research. pp. 1445–1450.
Khan AW, Khan A, and Ahmed T. (2016) Anticonvulsant, anxiolytic, and sedative activities of Verbena Officinalis. Front Pharmacol. 7:499.
Perviz S, Khan H, and Pervaiz A. (2016) Plant alkaloids as an emerging therapeutic alternative for the treatment of depression. Front Pharmacol. 7:28.
Zhu HL, Wan JB, Wang YT, et al. (2013) Medicinal compounds with antiepileptic/anticonvulsant activities. Epilepsia. 55(1):12463.
Peng WH, Lo KL, Lee YH, Hung TH, and Lin YC. (2007) Berberine produces antidepressant-like effects in the forced swim test and in the tail suspension test in mice. Life Sciences. 81(11):933-938.
Lambrecq V, Villég F, Marchal C, et al. (2012) Refractory status epilepticus: electroconvulsive therapy as a possible therapeutic strategy. Seizure. 21(9):661-4.
Kamel H, Cornes SB, Hegde M, Hall SE, and Josephson SA (2010) Electroconvulsive therapy for refractory status epilepticus: a case series. Neurocritical Care. 12(2):204-210.
Ben-Menachem E. (2002) Vagus-nerve stimulation for the treatment of epilepsy The Lancet Neurology. 1(8):477-482.
Grimonprez A, Raedt R, Baeken C, Boon P, and Vonck K. (2015) The antidepressant mechanism of action of vagus nerve stimulation: evidence from preclinical studies. Neuroscience and Biobehavioral Reviews. 56:26–34.
Laxpati NG, Kasoff WS, and Gross RE. (2014) Deep brain stimulation for the treatment of epilepsy: circuits, targets, and trials. Neurotherapeutics. 11(3):508-526.
Holtzheimer PE and Mayberg HS. (2011) Deep brain stimulation for psychiatric disorders. Annu Rev Neurosci. 34:289-307.
Gillig P, Sackellares JC, and Greenberg HS. (1988) Right hemisphere partial complex seizures: mania, hallucinations, and speech disturbances during ictal events. Epilepsia. 29:26–29.
Kaplan PW. (2003) Delirium and epilepsy. Dialogues Clin Neurosci. 5(2):187-200.
Beletsky V and Mirsattari SM. (2011) Epilepsy, mental health disorder, or both? Epilepsy Research and Treatment. (Article ID 163731).
Matsuura M, Adachi N, Oana Y, et al. (2004) A polydiagnostic and dimensional comparison of epileptic psychoses and schizophrenia spectrum disorders. Schizophrenia Research. 69(2-3):189–201.
Lado FA and Moshé SL. (2008) How do seizures stop? Epilepsia. 49(10):1651-54.
Wharton W, Gleason CE, and Asthana S. (2012) Neurobiological underpinnings of the estrogen - mood relationship. Curr Psychiatry Reviews. 8(3):247–256. (p. 4).
Huo L, Straub RE, Schmidt PJ, et al. (2007) Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene. Biological Psychiatry. 62(8):925-933.
Ting JT and Feng G. (2011) Neurobiology of obsessive-compulsive disorder: insights into neural circuitry dysfunction through mouse genetics. Curr Opin Neurobiol. 21(6):842-848.
Lindgren KA, Larson CL, Schaefer SM, et al. (1999) Thalamic metabolic rate predicts EEG alpha power in healthy control subjects but not in depressed patients. Biological Psychiatry. Vol. 45:943-952.
Plana-Ripoll O, Pedersen CB, and McGrath JJ. (2019) Exploring comorbidity within mental disorders among a Danish national population. JAMA Psychiatry. 76(3):259-270.
Cassidy CM, Balsam PE, Weinstein JJ, et al. (2018) A perceptual inference mechanism for hallucinations linked to striatal dopamine. Current Biology. 28(4):503-514.e4.
Gittelman JX, Perke DJ, and Portfors CV. (2013) Dopamine modulates auditory responses in the inferior colliculus in a heterogeneous manner. J Assoc Res Otolaryngol. 14(5):719-29.
Hargreave E. (2006). The neuroplasticity phenomenon of kindling. http://hargreaves.swong.webfactional.com/kindle.htm. (Accessed 5/19/18).
Begh M, Beghi E, and Cornaggia CM. (2016) Epilepsy in psychiatric disorders. In: Mula M. (eds) Neuropsychiatric Symptoms of Epilepsy. Neuropsychiatric symptoms of neurological disease. pp. 289-302. Springer, Cham Publishing Company. ISBN: 978-3-319-22158-8.
Josephson CB, Lowerison M, Vallerand I, et al. (2017). Association of depression and treated depression with epilepsy and seizure outcomes: a multicohort analysis. JAMA Neurol. 74(5):533-539.
Lopez AY, Wang X, Xu M, et al. (2017) Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder. Molecular Psychiatry. 22:1464–1472.
Pearce JMS. (2001) Bromide, the first effective antiepileptic agent. Journal of Neurology, Neurosurgery & Psychiatry. 72(3).
Substance Abuse and Mental Health Services Administration, Office of Applied Studies, Rockville, MD. (2008) The NSDUH Report: Substance use and dependence following initiation of alcohol or illicit drug use.
Saisan J, Smith M, Robinson L, and Segal J. (2018) Substance abuse and mental health issues: dealing with drug or alcohol addiction and co-occurring mental health problems. https://www.helpguide.org/articles/addictions/substance-abuse-and-mental-health.htm. (Accessed 9/25/18).
Schäfers M and Sorkin L. (2008) Effect of cytokines on neuronal excitability. Neuroscience Letters. 437(3):188-193.
Vezzani A and Viviani B. (2015) Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology. 96(Part A):70-82.
Galic MA, Riazi K, and Pittman QJ. (2012) Cytokines and brain excitability. Frontiers in Neuroendocrinology. 33(1):116-125.
Lu S, Peng H, Wang L, et al. (2013) Elevated specific peripheral cytokines found in major depressive disorder patients with childhood trauma exposure: a cytokine antibody array analysis. Compr Psychiatry. 54(7):953-61.
Buckley PF and Miller BJ. (2018) Rheumatoid arthritis drugs for schizophrenia? Psychiatric Annals. 48(5):232-236.
Boorman E, Romano GF, Russell A, Mondelli V, and Pariante CM. (2015). Are mood and anxiety disorders inflammatory diseases? Psychiatric Annals. 45(5):240-248.
Biskin RS and Paris J. (2013) Comorbidities in borderline personality disorder. Psychiatric Times. 30(1).
Aghajanian GK and Marek GJ. (1997) Serotonin induces excitatory postsynaptic potentials in apical dendrites of neocortical pyramidal cells. Neuropharmacology.36(4-5):589-599.
Cardamone L, Salzberg MR, Koe AS, et al. (2014) Chronic antidepressant treatment accelerates Kindling epileptogenesis in rats. Neurobiol Dis. 63:194-200.
Cardamone L, Salzberg MR, and Jones NC (2013) Antidepressant therapy in epilepsy: can treating the comorbidities affect the underlying disorder? Br J Pharmacol. 168(7):1531-1554.
Preskorn SH and Fast GA. (1992). Tricyclic antidepressant-induced seizures and plasma drug concentration. J Clin Psychiatry. 53:160–162.
Pisani F, Spina E, and Oteri G. (1099). Antidepressant drugs and seizure susceptibility: from in vitro data to clinical practice. Epilepsia. 40(Suppl.10): S48–S56.
Ripoll LH. (3013) Psychopharmacologic treatment of borderline personality disorder. Dialogues Clin Neurosci. 15(2):213-224.
Olabi B and Hall J. (2010) Borderline personality disorder: current drug treatments and future prospects. Ther Adv Chronic Dis. 1(2):59-66.
Ripoll LH, Triebwasser J, and Siever LJ. (2011) Evidence-based pharmacotherapy for personality disorders. International Journal of Neuropsychopharmacology. 14(9):1257-1288.
Iranmanesh A, Lawson D, Dunn B, and Veldhuis JD. (2011) Glucose ingestion selectively amplifies ACTH and cortisol secretory-burst mass and enhances their joint synchrony in healthy men. J Clin Endocrinol Metab. 96(9):2882-2888.
Landsberg L. (1996) Insulin and the sympathetic nervous system in the pathophysiology of hypertension. Blood Press Supply. 1:25-29.
Milani P, Piu P, Popa T, et al. (2010) Cortisol-induced effects on human cortical excitability. Brain Stimul. 3(3):131-139.
Huang C-W, Huang C, Cheng J-T, Tsai J-J, and Wu SN. (2007) Glucose and hippocampal neuronal excitability: role of ATP-sensitive potassium channels. Journal of Neuroscience Research. 85(7):1468-1477.
Neilson S. (2018) Trying the Ketogenic Diet for mental health. 10 days of eating fat, for my mental health. SCIENCE OF US.https://www.thecut.com/2018 /01/trying-the-ketogenic-diet-for-mental-health.html. (Accessed 6/18/18).
Gedgaudas NT. (2009) Primal body, primal mind. Beyond the Paleo Diet for total health and a longer life. Healing Arts Press, Rochester, Vermont.
Masino SA, Kawamura M Jr, Wasser CD, Pomeroy LT, and Ruskin DN. (2009) Adenosine, Ketogenic Diet and epilepsy: the emerging therapeutic relationship between metabolism and brain activity. Curr. Neuropharmacol. 7(3):257- 268.
Aurora SK and Wilkinson F. (2007) The brain is hyperexcitable in migraine. Cephalalgia. 27(12)1442-1453.
Pathophysiology of migraine. https://migraine.com/pro/pathophysiology-of-migraine/ (Accessed 5/21/18).
Fleming KC and Volcheck MM. (2015) Central Sensitization Syndrome and the initial evaluation of a patient with fibromyalgia: a review. Rambam Maimonides Med J. 6(2): e0020.
Li Q, Han Y, Dy ABC, and Hagerman RJ. (2017) The gut microbiota and autism spectrum disorders. Front Cell Neurosci. 11:120.
Masterjohn C. (2008) High cholesterol and heart disease — myth or truth? The response-to-injury rabbit never developed atherosclerosis — why not? (Accessed 9/28/18)
Cohen S, Janicki-Deverts D, Doyle WJ, et al. (2012) Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. PNAS. 109(16):5995-5999.
Powell ND, Sloan EK, Bailey MT, et al. (2013) Social stress up-regulates inflammatory gene expression in the leukocyte transcriptome via β-adrenergic induction of myelopoiesis. PNAS. 110(41):16574-16579.
Friedman HS and Booth-Kewley S. (1987) Personality, Type A behavior, and coronary heart disease: the role of emotional expression. Journal of Personality and Social Psychology. 53(4):783-792.
Griner T. (1995) What's really wrong with you? A revolutionary look at how muscles affect your health. Avery Publishing. New York, NY.
Johnstone T, van Reekum CM, Urry HL, Kalin NH, Davidson, RJ. (2007) Failure to regulate: counterproductive recruitment of top-down prefrontal-subcortical circuitry in major depression. J. Neuroscience. 27(33):8877-8884.
Leuchter AF, Cook IA, Hunter AM, Cai C, and Horvath S. (2012) Resting-state quantitative electroencephalography reveals increased neurophysiologic connectivity in depression. 7(2):1-13. e32508.
Rigucci S, Serafini G, Pompili M, Kotzalidis GD, and Tatarelli R. (2009). Anatomical and functional correlates in major depressive disorder: the contribution of neuroimaging studies. World J Biol Psychiatry. 11(2 Pt 2):165–180.
Kimbrell TA, Ketter TA, George MS, et al. (2002) Regional cerebral glucose utilization in patients with a range of severities of unipolar depression. Biological Psychiatry. 51(3):237–252.
Crick F. (1984) Function of the thalamic reticular complex: the Searchlight Hypothesis. PNAS. 81:4586-4590.
Hamilton JP, Etkin A, Furman DJ, et al. (2012) Functional neuroimaging of major depressive disorder: a meta-analysis and new integration of baseline activation and neural response data. Am J Psychiatry. 169(7):693-703.
Erlij D, Acosta-García J, Rojas-Márquez M, et al. (2012) Dopamine D4 receptor stimulation in GABAergic projections of the globus pallidus to the reticular thalamic nucleus and the substantia nigra reticulata of the rat decreases locomotor activity. Neuropharmacology. 62(2):1111-1118.
THALAMUS: http://zlab.rutgers.edu/modules/teaching/docs/Thalamus/Thalamus%20Lecture.pdf. (Accessed 5/19/18).
Carlsson A. (1988) The current status of the dopamine hypothesis of schizophrenia. Psychopharmacology. 1:179-186.
Al-Shargie F, Kiguchi M, Badruddin N, et al. (2016). Mental stress assessment using simultaneous measurement of EEG and fNIRS. Biomed Opt Express. 7(10):3882-3898.
Wada JA, Sato M, and Corcoran ME. (1974) Persistent seizure susceptibility and recurrent spontaneous seizures in kindled cats. Epilepsia. 15(4):465-478.
Baliki MN, Geha PY, Apkarian AV, and Chialvo DR. (2008) Beyond feeling: chronic pain hurts the brain, disrupting the Default-Mode network dynamics. Journal of Neuroscience. 28(6):1398-1403.
Kang DH, Son JH, and Kim GC. (2010) Neuroimaging studies of chronic pain. Korean J Pain. 23(3):159.
Martucci KT, Ng P, and Mackey S. (2014) Neuroimaging chronic pain: what have we learned and where are we going? Future Neurol. 9(6):615-626.
Crone EA and Ridderinkhof KR. (2011) The developing brain: from theory to neuroimaging and back. Developmental Cognitive Neuroscience. 1(2):101-109.
Ferreira, MAR, O’Donovan MC, and Sklar P. (2008) Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet. 40(9):1056-1058.
Woolf, CJ. (2011) Central sensitization: implications for the diagnosis and treatment of pain. Pain. 153(3 suppl): S2-15.
ANK3 ankyrin 3 [Homo sapiens (human)] - Gene- NCBI Gene ID: 288. https://www.ncbi.nlm.nih.gov/gene/288. (Accessed 11/1/18).
Yuan A, Yi Z, Wang Q, et al. (2012) ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis. Am J Med Genet B Neuropsychiatr Genet. 159B(8):997-1005.
Lopez AY, Wang X, Xu M, et al. (2017) Ankyrin-G isoform imbalance and interneuronopathy link epilepsy and bipolar disorder. Mol Psychiatry. 22(10):1464–1472.
Green EK, Grozeva D, Jones I, et al., Wellcome Trust Case Control Consortium, Holmans, PA, Owen, MJ, O'Donovan, MC, and Craddock N. (2010) The bipolar disorder risk allele at CACNA1C also confers risk of recurrent major depression and of schizophrenia. Mol Psychiatry. 15(10):1016-1022.
Liu Y, Blackwood DH, Caesar S, et al. (2011) Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Mol Psychiatry.16(1).
Iqbal Z, Vandeweyer G, van der Voet M, et al. (2013) Homozygous and heterozygous disruptions of ANK3: at the crossroads of neurodevelopmental and psychiatric disorders. Human Molecular Genetics. 22:1960-1970.
Bahremand A, Ziai P, Khodadad TK, et al. (2010) Agmatine enhances the anticonvulsant effect of lithium chloride on pentylenetetrazole-induced seizures in mice: Involvement of L-arginine/nitric oxide pathway. Epilepsy & Behavior. 18(3):186-192.
Brown P, Kashiviswanath S, Huynh A, et al. (2016) Lithium therapy in comorbid temporal lobe epilepsy and cycloid psychosis. Oxf Med Case Reports. 2016(12): omw089.
Shukla S, Mukherjee S, and Decina P. (1988) Lithium in the treatment of bipolar disorders associated with epilepsy: an open study. J Clin Psychopharmacol. 8(3):201-204.
Subramanian J, Dye L, and Morozov, A. (2013) Rap1 Signaling Prevents L-Type Calcium Channel-Dependent Neurotransmitter Release. Journal of Neuroscience. 33(17):7245.
Santos M, D'Amico D, Spadoni O, et al. (2013) Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model. Journal of Neuroscience. 33(38):15259-15271.
Contractor A, Klyachko VA, and Portera-Cailliau C. (2015) Altered neuronal and circuit excitability in Fragile X syndrome. Neuron. 87(4):699-715.
O’Brien NL, Way MJ, Kandaswamy R, et al. (2014) The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder. Psychiatric Genetics. 24:277–278.
Schizophrenia Working Group of the Psychiatric Genomics Consortium: Ripke S, Neale BM, and O’Donovan MC. (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature. 511(7510):421-427.
Freedman R, Coon H, Myles-Worsley M, et al. (1997) Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. PNAS. 94(2):587–592.
Pizzarelli R and Cherubini E. (2011) Alterations of GABAergic signaling in autism spectrum disorders. Neural Plast. 1011:157193.
Ogawa S, Tsuchimine S, and Kunugi H. (2018) Cerebrospinal fluid monoamine metabolite concentrations in depressive disorder: a meta-analysis of historic evidence. Journal of Psychiatric Research. 105:137-146.
Shepard RD, Langlois LD, Browne CA, et al. (2018) Ketamine reverses lateral habenula neuronal dysfunction and behavioral immobility in the forced swim test following maternal deprivation in late adolescent rats. Front Synaptic Neurosci. 10:39.
Popovic J and Mestrovic A. (2014) Habenula – the role in depression. Gyrus. 3(2):97-99.
Authement ME, Langlois LD, Shepard RD, et al. (2018) A role for corticotropin-releasing factor signaling in the lateral habenula and its modulation by early-life stress. Sci. Signal. 11(520):6480.
Aizawa H, Cui W, Tanaka K, and Okamoto H. (2013) Hyperactivation of the habenula as a link between depression and sleep disturbance. Frontiers in Human Neuroscience. 7:1-6.
Wang R and Aghajanian G. (1977). Physiological evidence for habenula as major link between forebrain and midbrain raphe. Science. 197:89–91.
Christoph G, Leonzio R, and Wilcox K. (1986). Stimulation of the lateral habenula inhibits dopamine-containing neurons in the substantia nigra and ventral tegmental area of the rat. J Neurosci. 6(3):613–619.
Herrick DD, and Sateia MJ. (2016) Insomnia and depression: a reciprocal relationship. Psychiatric Annals. 46(3):164-176.
Engström G, Alling C, Blennow K, Regnell G, and Träskman-Bendz L. (1999) Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls. Eur. Neuropsychopharmacol. 9(5):399-405.
Pande AC, Pollack MH, Crockatt J, et al. (2000) Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol. 20(4):467-471.
Pollack MH, Matthews J, and Scott EL (1998) Gabapentin as a potential treatment for anxiety disorders. American Journal of Psychiatry. 155(7):992-993.
Strawn, JR and Geracioti TD Jr (2007) The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic. Neuropsychiatr Dis Treat. 3(2):237-243.
Baetz M and Bowen RC. (1998) Efficacy of divalproex sodium in patients with panic disorder and mood instability who have not responded to conventional therapy. Can J Psychiatry. 43(1):73-77.
Cournoyer J. (1986) Rapid response of a disorder to the addition of lithium carbonate: panic resistant to tricyclic antidepressants. Can J Psychiatry. 31(4):335-8.
Pande AC, Davidson JR, Jefferson JW, et al. (1999) Treatment of social phobia with gabapentin: a placebo controlled study. Clin Psychopharmacol. 19(4):341-348.
Berlant, J. (2006) Topiramate as a therapy for chronic posttraumatic stress disorder. Psychiatry (Edgmont). 3(3):40-45.
Wang HR, Woo YS, and Bahk W-M. (2014) Potential role of anticonvulsants in the treatment of obsessive–compulsive and related disorders. Psychiatry and Clinical Neurosciences. 68:723-732.
Mason BJ, Quello S, Goodell V, et al. (2014) Gabapentin Treatment for Alcohol Dependence. A Randomized Clinical Trial. JAMA Intern Med. 174(1):70-77.
Marks DM, Patkar AA, Masand PS, and Pae C-U. (2009) Does pregabalin have neuropsychotropic effects?: a short perspective. Psychiatry Investig. 6(2):55-58.
Hirschfeld R, Lewis L, and Vornik L. (2003) Perceptions and impact of bipolar disorder: how far have we really come? Results of the National Depressive and Manic-Depressive Association 2000 survey of individuals with bipolar disorder. J Clin Psychiatry. 64(2):161-174.
Dagani J, Signorini G, Nielssen O, et al. (2016) Meta-Analysis of the Interval between the Onset and Management of Bipolar Disorder. The Canadian Journal of Psychiatry. 64(4).
Campbell D. (2012) People with bipolar disorder may wait 13 years for diagnosis. The Guardian. https://www.theguardian.com/society/2012/jun/27/bipolar-disorder-diagnosis-survey. (Accessed 10/7/18).
Carpenter WT Jr, Buchanan RW, Kirkpatrick B, and Breier AF. (1999) Diazepam treatment of early signs of exacerbation in schizophrenia. Am J Psychiatry. 156(2):299-303.
Wassef AA, Dott SG, Harris A, et al. (2000) Randomized, placebo-controlled pilot study of divalproex sodium in the treatment of acute exacerbations of chronic schizophrenia. J Clin Psychopharmacol. 20:357–361.
Basan A, Kissling W, and Leucht S. (2004) Valproate as an adjunct to antipsychotics for schizophrenia: a systematic review of randomized trials. Schizophr Res. 70:33–37.
Gallagher RM, Mueller LL, and Freitag FG. (2002) Divalproex sodium in the treatment of migraine and cluster headaches. J Am Osteopath Assoc. 102(2):92.
Boomershine CS. (2010) Pregabalin for the management of fibromyalgia syndrome. J Pain Res. 3:81-88.
Tremont-Lukats and Beckonja MC. (2000) Anticonvulsants for neuropathic pain syndromes: mechanisms of action and place in therapy. Drugs. 60(5):1029-1052.
Wood JG, Crager JL, Delap CM, and Heiskell KD. (2007) Beyond methylphenadate: nonstimulant medications for youth with ADHD. J Atten Disord. 11(3):341-350.
Eatmon CV and Daniel JS. (2014) Should you use an anticonvulsant to treat impulsivity and aggression? Current Psychiatry. 13(4):49-51.
Hillhouse TM and Porter JH. (2015) A brief history of the development of antidepressant drugs: from monoamines to glutamate. Exp Clin Psychopharmacol. 23(1):1-21.
Ramachandraih CT, Subramanyam N, Bar KJ, Baker G, and Yeragani VK. (2011) Antidepressants: from MAOIs to SSRIs and more. Indian Journal of Psychiatry. 53(2):180-182.
Kreston R. (2016) The psychic energizer!: the serendipitous discovery of the first antidepressant - Body Horrors. http://blogs.discovermagazine.com/bodyhorrors/2016/01/27/2081/. (Accessed 10/2/18).
Neumeister A, Nugent AC, Waldeck T, et al. (2004) Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry. 61:765-773.
Delgado PL, Price LH, Miller HL, et al. (1994) Serotonin and the Neurobiology of Depression. Effects of tryptophan depletion in drug-free depressed patients. Arch Gen Psychiatry. 51:865-874.