Advances in schizophrenia

advancements in schizophrenia treatment

1. Presenter : Dr. Shravan Kumar Moderator : Prof. R. K. Gaur

2. INTRODUCTION Schizophrenia is common, chronic and frequently devastating neuropsychiatric disorder, affecting about 1% of the world’s general population. It imposes a disproportionately large economic burden in terms of hospitalization, chronic treatment and rehabilitation, and lost productivity. It is among the ten leading causes of disability worldwide.

3. The onset of schizophrenia ranges from mid to late adolescence through; it occurs more often in males and affects them more severely than it does females. Although minor physical anomalies and subtle motor, social or cognitive impairments are often observed during the premorbid stage of the illness, these differences generally fail to place individuals outside the normal range of functioning.

4. After the onset of the full syndrome substantial functional deterioration ( e.g. work, interpersonal relationships, or self care) typically occurs, especially during the first five to ten years, and then clinical deterioration reaches a plateau. Schizophrenia is further defined by characteristic but nonspecific disturbances in the form and content of thought, perception, cognition, and emotion, sense of self, volition, social relationship, and psychomotor behavior

5. Francisco Goya – The Madhouse 1812

6. Current treatment modalities have certain limitations: about 30% of patients with schizophrenia are refractory. Negative symptoms like alogia , avolition , anhedonia , attentional impairment and executive dysfunction can be worsened by medication and coexisting depression. There are no effective remedies for primary negative symptoms.

7. Cognitive impairments, primarily in the areas of attention, information processing, problem solving, processing speed, verbal/visual learning and working memory show poor response to the treatment with either first generation or second generation antipsychotic. A majority of the patients have relapsing and remitting course even while on medication.

8. The development of effective treatments for these psychopathological domains is of critical clinical importance since they account for much of the long term morbidity and poor functional outcome in schizophrenia. The relative lack of efficacy for these domains has led to the search for alternative pathophysiological hypothesis and treatment of negative symptoms and cognitive impairments.

9. A century ago we had large public institutions for severe mental illness, tuberculosis and leprosy. Of these three, today only mental illness, especially schizophrenia, remains unchanged in prevalence and disability . Sustained recovery is less than 14% within the first 5 years following a psychotic episode . Thomas Insel ; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552

10. OTHER CONDITIONS RESEMBLING ACUTE SCHIZOPHRENIA Tumors: temporal lobe (auditory), occipital lobe (visual), limbic and hypothalamus (delusions) Seizures: temporal lobe, grand-mal (post- ictal psychosis) Parkinson’s disease Huntington’s disease Multiple Sclerosis Amyotrophic lateral sclerosis Neurosyphilis Meningitis/encephalitis HIV Hypo/hyperthyroidism

11. Hypo/hyper parathyroidism Adrenal disorders (Addison’s or Cushing’s disease) Systemic Lupus erythematosus Sodium/potassium inbalance Hepathic encephalopathy Uremic encephalopaty Acute intermittent porphyria Vitamin B12 or folate deficiency Heavy metal poisoniong Wilson’s disease Dialysis

12. SUBSTANCES LEADING TO SCHIZOPHRENIA LIKE CONDITION Amphetamines, hallucinogens or cannabis Corticosteroid treatment Alcohol intake Dopaminergic drugs (L-dopa, Amantadine ) Interferon Anticholinergics Cardiovascular drugs

13. Anesthetics Antimalarial drugs Antituberculous drugs: d- cycloserine , ethambutol , isoniasid Antibiotics: cprofloxacin Antivirals : HIV medications ( efavirenz , acyclovir) Antineoplasic drugs Sympatomimetics Pain medications ( meperidine , pentazocine , indomethacin )

14. Neurochemical transmission in the dopaminergic system, especially via D2 receptors, and related changes in postsynaptic signal transduction are very important in both the development of schizophrenia and its current pharmacotherapeutic treatment with antipsychotic drugs. Along with D3 and D4 receptors, dopamine D2 receptors and their synaptic localization remain importance in schizophrenia pharmacotherapy.

15. Serotonergic 5-HT2A and 5-HT2C receptor blockage is the mechanism of action of new-generation antipsychotics mechanism of action. There is a functional interaction between the serotonergic and dopaminergic systems and blockage of 5-HT2A receptors can reinforce dopaminergic activity. In contrast to classic antipsychotic drugs, many recently developed atypical antipsychotics bind to 5-HT2A receptors more than to dopamine D2 receptors and bind with higher affinity than classical antipsychotics.

16. D2 ANTAGONIST ACTIONS: CONVENTIONAL/ATYPICAL ANTIPSYCHOTIC D2

17. - D2 antagonist action -5HT2A antagonist action atypical antipsychotic 5HT2A D2

18. Neurodevelopmental dysfunctions in the GABAergic and glutamatergic systems are also related to the development of schizophrenia. Contemporary research into the etiopathogenesis of schizophrenia focuses on the expanding role of neurogenesis and neurotrophic factors, primarily in the dopaminergic system, but also in the serotonergic , GABAergic , and glutamatergic systems.

19. Schizophrenia is a collection of neurodevelopmental disorders that involve alterations in brain circuits during early development. Psychosis is a late occurrence in schizophrenia. Preventive approaches seen as the main intervention. Thomas Insel ; Rethinking Schizophrenia; Nature vol 468, November 201; doi:10.1038/nature09552

20. Birth cohort studies demonstrate that individuals who develop schizophrenia differ from the general population on a range of developmental indices some of which occur as early as the first year of life. Joy Welham,2 Matti Isohanni,3 Peter Jones,4 and John McGrath; The Antecedents of Schizophrenia: A Review of Birth Cohort Studies; Schizophr Bull. 2009 May; 35(3): 603–623, . doi : 10.1093/ schbul /sbn084

21. Stages of Schizophrenia as a Neurodevelopmental Disorder

22. SCHIZOPHRENIA AND BRAIN TISSUE LOSS MRI IMAGE OF AN AVERAGED PROFILE OF BRAIN TISSUE LOSS FROM A GROUP OF PATIENTS WITH EARLY- ONSET SCHIZOPHRENIA (5 YEARS INTERVAL)

23. MECHANISM OF BRAIN TISSUE LOSS Schizophrenia is a disease of progressive reductions in grey matter, and the more lost, the worse the outcome. Schizophrenia is not a disease that kills massive amounts of cells, the way Alzheimer’s disease does. In schizophrenia primarily there is a loss of cell processes, because of low levels of neurotrophins e.g. NT-3, NGF, GDNF, BDNF

24. CORTICAL PYRAMIDAL NEURONS

25. REALISTIC PERSPECTIVE ON GENES IN SCHIZOPHRENIA There is no gene for schizophrenia, bipolar disorder, depression or anxiety and there will never be one. Genes do not code for psychiatric illnesses or for behaviors or for symptoms of psychiatric illnesses. Genes operate at a very basic cellular level. They code for proteins that may lead to subtle molecular abnormalities in cells.

26. Genes are Risk Factors for Mental Illness Genes do not respect the boundaries of psychiatric disorders or even the boundaries of medical disciplines. For instance most risk genes for schizophrenia are present also in bipolar disorder, schizoaffective disorder, ASD, Alzheimer’s disease and anxiety. There are vulnerability genes as well as resilience genes. The chance that two patients with schizophrenia will have exactly the same combination of mutations is small.

27. Deletion of 22q11.2 is one of the highest risk factors for schizophrenia and it also leads to Velo -Cardio-Facial Syndrome (VCFS). VCFS leads to schizophrenia in 33% cases.

28. Spontaneous genetic mutations or “de novo” mutations play a significant role in schizophrenia. The function of the mutated gene and when the gene is expressed are critically important in determining the risk for schizophrenia.

29. RESEARCH DOMAIN CRITERIA (RDOC) RDoC is an experimental approach to the classification of mental disorders that incorporates multiple dimensions: behavior, thought patterns, neurobiological measures, and genetics. The aim of the project is to develop a more accurate diagnostic system.

30. SCHIZOPHRENIA AND METABOLISM Normally the brain uses glucose as its main energy source, with ketone bodies as an alternative. In schizophrenia brain energy supply is scarce due to mitochondrial dysfunction. The brain shifts its energy supply towards ketone bodies, and fatty acid metabolism. Liver metabolism is shifted towards producing the necessary ketone bodies.

31. METABOLIC BIOMARKERS IN SCHIZOPHRENIA The following set of metabolic biomarkers have identical sensitivity and specificity as the MSE: Glycerate Eicosenoic acid Beta- hydroxybutirate Pyruvate Cysteine Urine beta hydroxybutirate Potential Metabolite Markers of Schizophrenia; J. Yang et al.; Molecular Psychiatry(213) 18, 67-78; doi:10.1038/mp.131

32. FDA APPROVED ANTIPSYCHOTICS THIS DECADE Aripiprazol (2002) Fazaclo (Sept, 14, 2005) Paliperidone (December 19, 2006) Illoperidone (May 7, 2009) Asenapine (August 15, 2009) Lurasidone (October 29, 2010)

33. NEW DRUGS IN THE PIPELINE Aspirin Minocycline Raloxifene Estrogen N- acetylcysteine

34. ILOPERIDONE Indicated for acute schizophrenia in adults. Dosing: Day 1--1mg bd Day2 –2mg bd Day3—4mg bd Day4—6mg bd Day5—8mg bd Day6—10mg bd Day7—12mg bd

35. Tolerability Moderate effects on body weight - Iloperidone -induced changes in weight are independent from significant changes in glucose or lipid levels Low rate of akathisia Slow titration and careful monitoring of orthostatic hypotension are required -Especially in the elderly or when used in combination with other medications that may induce orthostasis (e.g., diuretics, TCA) Significant risk of QTc prolongation Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

36. ASENAPINE Indicated for acute schizophrenia. Sublingual Formulation -bioavailability when swallowed is very low -avoid eating or drinking for 10 min after administration Typical dose -Schizophrenia 5 mg BID -Bipolar mania 10 mg BID May be useful as a rapid-acting PRN antipsychotic No dose adjustment necessary in patients with moderate hepatic or renal impairment Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

37. Tolerability: Limited effects on weight -small, non-significant effects on fasting glucose levels have been observed -no clinically significant effects on total cholesterol or fasting triglycerides have been observed Slightly elevated risk of akathisia and EPS Oral hypoesthesia and somnolence are not uncommon May induce orthostatic hypotension and syncope Marginal effects on QTc interval Benign effects on prolactin . Tarazi F, Stahl SM Expert Opinion Pharmacotherap 2012 Epub ahead of print

38. LURASIDONE Recommended starting dose 40 mg/day Maximum recommendined dose was originally 80 mg/day, now 160. - In May 2012 FDA approved an extended dose range of 40-160 mg/day for schizophrenia -120 mg tablet currently in development No titration required Should be taken with food (at least 350 calories) Should not exceed 40 mg/day in patients with moderate to severe renal or hepatic impairment.

39. Tolerability: Benign metabolic profile - minimal changes in body weight -no significant changes in total cholesterol, triglycerides, LDLs, HDLs or fasting glucose Risk of akathisia at higher doses No QTc prolongation Small increase in prolactine Administering Lurasidone at night may reduce side-effects

40. CARIPRAZINE D2 partial agonist more of an antagonist than Aripiprazole In late stage clinical testing for schizophrenia, acute bipolar mania, bipolar depression and treatment resistant depression higher doses for schizophrenia and mania (antagonist actions) lower doses for depression (agonist action) Stronger affinity for D3 than D2 receptors Few metabolic side effects and low risk for EPS Long lasting metabolite. Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4 th ed 2011

41. BREXPIPRAZOLE D2 partial agonist -more of an antagonist than Aripiprazole Very low risk for EPS and rare akathisia so far despite strong affinity for D2 receptors -possibly due to potent 5HT2A antagonism, 5HT1A antagonism and alpha 1 antagonism Potential treatment for agitation and psychosis in dementia Stahl SM Stahl’s Essential Psychopharmacology; The Prescriber’s Guide 4 th ed 2011

42. ASPIRIN Aspirin is irreversible inhibitor of both COX-1 and COX-2. It is more potent in its inhibition of COX-1 than COX-2, and targeting COX-2 alone may be a less viable therapeutic approach in neuropsychiatric disorders such as depression. COX-2 inhibition decreases the production of PGE-2, which drives the negative immunoregulatory effects on ongoing inflammatory responses. Lipoxins  A new genus of lipid mediators that actively limit inflammation and promote resolution.

43. Aspirin as adjuvant therapy  ↓ symptoms of schizophrenia spectrum disorders ( Laan et al., 2010) Largest effect of adjuvant aspirin ( Laan et al., 2010) Most altered immune balance Shorter disease durations Future studies  Patients with recent onset of disease & more disturbed immune functions

44. MINOCYCLINE

45. Addition of minocycline to atypical antipsychotic drugs in early schizophrenia ( Oya et al., 2014) S ignificant efficacy on negative symptoms ( Ghanizadeh et al., 2014) Slight effect on the attention domains of patients with schizophrenia (Liu et al., 2014) Treatment with minocycline (3mg/kg/day)  Normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behaviour ( Mattei et al., 2014)

46. RALOXIFENE The role of SERM in the treatment of positive psychotic symptoms has been documented ( Kulkarni et al., 2008) Raloxifene  E xhibit agonistic and protective action on the brain by modulating the monoaminergic neurotransmission of dopamine, serotonin and GABA (Garcia-Segura et al., 2001)

47. Addition of Raloxifene (60 mg/day) to regular antipsychotic treatment ↓ negative, positive & general psychopathological symptoms in comparison with women receiving antipsychotic medication alone ( Usall et al., 2011) Advantage over estrogens  Patients in Raloxifene group did not have more adverse effects than patients in the placebo group (Chua et al., 2005)

48. ESTROGEN Short term  rapid membrane effects by altering functional activity in the dopaminergic synapse ( di paolo , 1994) Long term  modifies synthesis in dopamine receptors ( di paolo , 1994) Estrogen alters serotonergic system ( moses et al., 2000) Estrogen promotes neuronal regeneration & blocks mechanisms of neuronal death ( doncarlos et al., 2009)

49. N -ACETYL CYSTEINE Glutathione is a major antioxidant that protects cells against oxidative stress (Meister and Anderson, 1983) Glutathione potentiates NMDA receptors ( Choi and Lipton, 2000; Kohr et al, 1994) In schizophrenia, glutathione dysregulation  NM DA receptor hypofunction

50. NAC (GSH precursor)  I mproved auditory cortical functioning as indexed by the mismatch negativity (Lavoie et al., 2008) Mismatch negativity (MMN)  A n auditory evoked potential (AEP) component related to NMDA receptor function Participants treated with NAC  Improvements in insight, self-care, social interaction, motivation, volition, psychomotor stability and stabilization of mood (Berk et al., 2010)

51. CHOLINERGIC AGENTS Ach. modulates dopamine transmission in striatum, where dopamine dysregulation may contribute to both positive and negative symptoms and in the cortex, where dopamine transmission deficits have been postulated to contribute to cognitive deficits, particularly in attention, learning and memory. In a recent SPECT study, muscarinic receptors were significantly reduced in the cortex, thalamus, and basal ganglia in patients with schizophrenia.

52. Nicotine receptors Nicotine administration improves various measures of cognition that may ease some of the side effects of anti-psychotics. Freedman et al tested a cholinergic nicotinic partial agonist selective for the alfa7-selective agonist DMXB-A, in 31 clinically stable outpatients with chronic schizophrenia receiving maintenance antipsychotic medications, using a placebo controlled crossover design.

53. The investigators did not find significant improvement on their primary outcome measure of cognition, the MATRICS consensus battery but they did see a therapeutic effect on negative symptoms measured by scale for the assessment of negative symptoms. The partial agonist activity of DMXB-A may help to minimize the problem of tachyphylaxis observed with full agonist nicotine. Though, there is one recent study which shows positive effect on neurocognition .

54. Muscarinic receptors Among 5 types of these receptors (M1-M5), M1 is linked to cognition in schizophrenia and is most abundant of muscarinic receptors in forebrain and hippocampus. Action at M1 receptors has been proposed to be a major contributor in cognition enhancement effects of clozapine which is a weak partial agonist at M1 receptor. Its metabolites including clozapine -N-oxide and N- desmethylclozapine (NDMC) are in focus.

55. Acetylcholinesterase inhibiting agents The most frequently tested AChEIs is donepezil which has been found to be beneficial in cognitive impairment in small sampled controlled studies. Galantamine is another agent whose treatment is associated with selective benefit for attention and delayed memory and visual recognition. In addition to its selective action, galantamine is also a positive allosteric modulator of the alfa4beta4 and alfa7-nicotine receptors.

56. DOPAMINERGIC AGENTS Low doses of selective D1 agonists have cognition enhancing actions in nonhuman primates and short term administration of the D1 selective agonist, ABT-431 reversed working memory deficits with chronic antipsychotic therapy. D4 receptors may play an important role in impulsivity and working memory. High affinity of clozapine for these receptors led to speculation that these receptors may be clozapine’s ‘magic receptor’. However, clinical trials have not shown any appreciable efficacy in treatment of schizophrenia.

57. COMT is a postsynaptic enzyme that methylates and deactivates synaptically released catecholamines , particularly dopamine. A selective reversible inhibitor of COMT, tolcapone , has been reported to improve working memory in rodents and has been shown to improve cognitive dysfunction in patients with advanced Parkinsonism, though use is limited due to a risk of liver failure. Other COMT inhibitors are currently being investigated for cognitive dysfunctions in schizophrenia.

58. GLUTAMATERGIC TARGETS Glutamate is the primary excitatory neurotransmitter in brain contained as a neurotransmitter in about 60% of the brain neurons. Schizophrenia is associated with reduced glutamatergic neuro -transmission. Treatment requires to potentiate glutamatergic neurotransmission at either NMDA or non-NMDA receptors

59. 7 small-scale studies using full agonists ( Glycine at doses of 0.4-0.8 g/kg(30-60 g/d), D-serine 100mg/kg (2.1 g/d) and D- alanine 100mg/kg (7g/d)) with anti-psychotic medication have shown 20% improvement in negative symptoms. 2 small-scale studies with naturally occurring compound sarcosine at the dose of 2 g/d have shown 17% reduction in negative symptoms in patients stabilized on FGAs or SGAs.

60. Another agent LY2140023, a selective agonist for metabotropic glutamate 2/3 (mGluR2/3) when compared with placebo or olanzapine in a 4-week randomized controlled trial involving 196 patients with the dose of 80 mg/day showed better safety, tolerability and rapid onset of efficacy. Improvement in both positive and negative symptoms of schizophrenia was observed only after one week of treatment. EPS and weight gain were comparable with placebo.

61. SEROTONERGIC AGENTS Activating 5-HT1A receptors with a single dos of tandospirone , a 5-HT1A partial agonist, diminished explicit memory function in demented patients, though chronic administration of tandospirone enhanced verbal memory in patients with schizophrenia. 5-HT2A receptors are particularly abundant in the pyramidal neurons from cortical layer V, where they have been described to co localize with NMDA glutamate receptors, suggesting a role in modulating cognitive functions.

62. ALPHA -2 ADRENERGIC RECEPTORS Combined treatment of a typical antipsychotic with the highly selective alpha-2 adrenergic receptor antagonist, idazoxan , has been reported to produce a profile of antipsychotic activity similar to clozapine . Thus, as alpha-2-adrenergic receptor activity may be important in developing new drugs for schizophrenia that can improve cognition, balancingalpha-2-adrenergic receptor activity to achieve both antipsychotic and procognitive efficacy may be challenging.

63. GABA-A RECEPTORS Appropriately synchronized GABA neurotransmission in the dorsolateral prefrontal cortex is required for adequate working memory, suggesting that impairments in GABA-mediated inhibition could contribute to the cognitive impairments in schizophrenia. Studies have shown that antagonists or inverse agonists at alpha-5-containing GABA-A receptors may hold promise in the treatment of the cognitive dysfunction in schizophrenia.

64. NEUROSTEROID AND SIGMA RECEPTORS Neurosteroids , such as dehydroepiandrosterone (DHEA) and allopregnanolone , have been implicated in neuroprotection and enhancement of NMDA receptor neurotransmission, possibly through interaction with sigma-1 receptors, suggesting therapeutic potential for enhancing cognition in schizophrenia.

65. NK3 RECEPTOR ANTAGONIST Activation of NK3 receptors lead to activation and release of dopamine, 5HT and NA. Recent evidence suggests the clinical efficacy of two distinct NK3 receptor antagonists: osanetant and talnetant . These have been evaluated in double-blind, placebo controlled clinical trials in schizophrenia. Osanetant and talnetant represent distinct chemical classes and their properties are also markedly different, albeit with the common traits of NK3 receptor antagonism and a potentially similar efficacy in schizophrenia.

66. CANNABINOID RECEPTOR ANTAGONIST Some preclinical and clinical evidence suggests that cannabidiol may have anti schizophrenic potential mostly against negative symptoms.

67. AGMATINE Agmatine is a cationic amine synthesized from arginine via the enzyme arginine decarboxylase . Agmatine reduces morphine or alcohol withdrawal symptoms in rodents.NMDA receptor blockade may be responsible for this. These properties of agmatine (NMDA receptor blockade) can be useful in treating excitatory neuropsychiatric disorders. Agmatine could be a new target in the treatment of schizophrenia.

68. REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION It is thought to work by modifying cortical excitability, with high frequency or fast rTMS (>1Hz) having an activating effect on neuronal circuits and slow rTMS (<1Hz) an inhibitory effect . Data from different studies suggest that improvement in auditory hallucinations occur when rTMS of the left temporal parietal cortex is used to augment antipsychotic treatment. A recent mata -analysis concluded that rTMS efficiently reduces resistant auditory hallucinations in patients with schizophrenia.

69. For patients with prominent negative symptoms, small open studies of high frequency rTMS (10-20 Hz, given for 1-4 wks) of the left dorsolateral prefrontal cortex have reported beneficial effects on measures of negative symptoms with improvement being maintained after one month in one study. Although these findings are interesting and worthy for future research rTMS has not been approved for use in patients with schizophrenia and there is insufficient to recommend its use in clinical practice.

70. As a part of comprehensive treatment approach, psychosocial interventions can improve the course of schizophrenia when integrated with psychopharmacological treatments. Psychosocial interventions can provide additional benefits for patients in such areas as relapse prevention, improved coping skills, better social and vocational functioning, and ability to function more independently.

71. COGNITIVE BEHAVIOR THERAPY Several randomized controlled trials examining significant correlations between improvements in positive symptoms and some evidence of improved functioning but this did not quite reach significant.

72. SOCIAL SKILLS TRAINING Social skill and social competence can be viewed as protective factors in the vulnerability stress- protective factor model of schizophrenia. While social skills training may have a positive effect on social role functioning. It is not effective for reducing for reducing symptoms or preventing relapse. There are several reports of controlled studies in which social skills training significantly reduced relapse rates and symptom levels, but more research is needed to document the extent to which social skills training actually protects patients from relapse.

73. COGNITIVE REHABILITATION Several recent studies have shown decrease in positive and total symptoms score significantly on cognitive remediation therapy and negative symptoms did not change regardless of cognitive remediation therapy used. Some cognitive remediation therapies may be able to induce subjective improvement of cognitive functioning in patients with schizophrenia.

74. YOGA THERAPY A recent study by Duraiswamy et al, that yoga as add on treatment along with antipsychotic is beneficial in psychopathology, social and occupational functions, and quality of life. Though, it remains to establish whether benefits extend to cognitive deficits and are enduring.

75. GROUP MUSIC THEARPY It has been found that there are significant effects of music therapy on schizophrenia patient’s self-evaluation of their psychosocial orientation and for negative symptoms. No differences were found on quality of life.

76. FUTURE BIOLOGICAL TREATMENT ALGORITHM

77. A VISION FOR SCHIZOPHRENIA OVER THE NEXT DECADE

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