Valnoctamide in Mania
Condition: Mania; Schizoaffective Disorder, Manic Type
MeSH terms: Mania; Psychotic Disorders; Bipolar Disorder
Study type: Interventional
Phase: Phase 3

Summary: 
      Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its
      well-known teratogenicity limits its use in young women of childbearing age. According to
      toxicologic studies the teratogenicity of valproate stems from its free carboxylic group.
      Valnoctamide is an isomer and an analog of valpromide. Unlike valpromide, valnoctamide does
      not undergo a biotransformation to the corresponding free acid. It is also likely or at least
      possible that valnoctamide is anti-bipolar. In mice valnoctamide has been shown to be
      distinctly less teratogenic than valproate. An injection at day 8 of gestation produced only
      1% exencephaly (as compared to 0-1% in control mice and 53% in valproate treated mice).

      The investigators are performing a double-blind controlled trial of valnoctamide as an
      anti-bipolar drug. If shown to be anti-bipolar, valnoctamide could be an important valproate
      substitute for young women with bipolar disorder who are at risk of pregnancy. Patients newly
      admitted to the Beersheva Mental Health Center may participate if they meet Diagnostic and
      Statistical Manual of Mental Disorders - 4th edition (DSM-IV) criteria for mania or
      schizoaffective disorder, manic type. Patients admitted to the study are treated with
      risperidone at doses of the physicians' discretion beginning with 2 mg daily on days 1 and 2.
      Valnoctamide or placebo is begun at doses of 600 mg per day (200 mg three times daily) and
      increased to 1200 mg (400 mg three times daily) after four days.

      Weekly ratings by a psychiatrist blind to the study drug are conducted using the Brief
      Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale (YMS), and the Clinical Global
      Impression (CGI). Weekly blood is drawn for drug levels of valnoctamide to be measured by gas
      chromatography. Each patient receives valnoctamide or placebo for 5 weeks.

      Low teratogenic mood stabilizers are a high priority for current research.
    

Detailed description: 
      Valproic acid is a leading mood stabilizer for the treatment of bipolar disorder. Its
      well-known teratogenicity limits its use in young women of childbearing age (1-3). The
      alternative mood stabilizers such as lithium and carbamazepine also have teratogenic
      potential so the treatment of bipolar disorder in young women is problematic. The
      difficulties are particularly acute in those young women patients who respond well to
      anti-bipolar therapy and maintain or begin normal interpersonal and marital relations and
      desire to have children.

      One approach to this problem has been the search for valproic acid derivatives with less
      teratogenic potential (4). According to toxicologic studies the teratogenicity of valproate
      stems from its free carboxylic group (2, 3). Valpromide is an amide derivative of valproate
      without the suspect free carboxylic group. It was synthesized and marketed and has
      anticonvulsant efficacy, at least as good as valproic acid (1). There are some reports of its
      efficacy in bipolar disorder as well (5). In some animal species, only a small amount of
      valpromide is metabolized to valproic acid. However, in humans valpromide is metabolized to a
      large degree to valproic acid and so it does not solve the problem of teratogenicity (1, 6).

      Valnoctamide is an isomer and an analog of valpromide. Unlike valpromide, valnoctamide does
      not undergo biotransformation to the corresponding free acid (6-9). In animal studies it is
      at least as anticonvulsant as valproate and valpromide (1, 6, 10). It has been marketed as an
      anxiolytic and sedative in several European countries (as Nirvanil) including Italy, Holland
      and Switzerland but has not actively been promoted as an anticonvulsant. It was marketed in
      the USA as Axiquel by McNeil in the 1970's. Unfortunately, despite considerable efforts we
      have not been able to obtain pharmacovigilance data from this period. Given its equivalence
      to valproate and valpromide as an anticonvulsant in animal models of epilepsy (1, 6, 10), it
      is reasonable to assume that valnoctamide is also anticonvulsant in humans. It is also likely
      or at least possible that valnoctamide is anti-bipolar. In mice valnoctamide has been shown
      to be distinctly less teratogenic than valproate (11). Injection at day 8 of gestation
      produced only 1percent exencephaly (as compared to 0-1percent in control mice and 53 percent
      in valproate treated mice). Embryolethality rates showed similar results: 52 percent with
      valproate vs. 5percent in the controls and 2 percent with valnoctamide.

      Valnoctamide's patent is expired (12) and it is not the property of any major pharmaceutical
      company. Pharmaceutical company support cannot be obtained for our trial; therefore it is
      investigator initiated.

      Valnoctamide will be synthesized for our study by Banyan Chemical in India (which has been
      inspected by the FDA) by GLP (good laboratory practice) in a manner acceptable for human use
      by the Israel Ministry of Health (and in principle for an IND by the FDA). Banyan
      manufactures at the same site generic compounds, atenolol for instance, sold in the USA and
      distributed by international companies, Novartis for instance.

      Study Design:

      The study has been submitted to our Helsinki Committee and only patients who give informed
      written consent will be accepted. Patients newly admitted to the Beersheva Mental Health
      Center may participate if they meet DSM-IV criteria for mania or schizoaffective disorder,
      manic type. Minimal Young Mania Scale = 20. Only patients admitted to the hospital within the
      previous 72 hours will be eligible for the study. Exclusion criteria will be as in previous
      studies of mania with this design by our group (15-17) and will include drug abuse, active
      physical illness, and of course pregnancy.

      Patients admitted to the study will be treated with risperidone at doses of physicians'
      discretion beginning with 2 mg daily on days 1 and 2. On days 3 and 4 the risperidone dose
      could be increased to a maximum of 4 mg daily or decreased to 1mg daily. On days 5 to study
      end the dose could be increased to a maximum of 6 mg daily or decreased to a minimum of 1mg
      (see ref #18). Dose of risperidone will be a secondary outcome measure (see reference #15 &
      #16). No washout from previous medication is required but patients who received depot
      neuroleptics within the past 2 weeks or more than 300 mg of chlorpromazine equivalents in the
      past three days will be excluded. Trihexyphenidyl (up to 4 mg daily) will be available as
      necessary for extrapyramidal symptoms and benzodiazepines for sleep. Valnoctamide or placebo
      will be begun at doses of 600 mg per day (200 mg three times daily) and increased to 1200 mg
      (400 mg three times daily) after four days. This dose is based on relative anticonvulsant
      effects of valproate and valnoctamide in animal studies (1, 6, 10).

      Patients will receive valnoctamide or identical capsules of placebo as assigned by the
      control psychiatrist according to random order; manic and schizoaffective manic patients will
      be randomized separately. Weekly ratings by a psychiatrist blind to the study drug will be
      conducted using the Brief Psychiatric Rating Scale (BPRS), the Young Mania Rating Scale
      (YMS), and the Clinical Global Impression (CGI). Primary outcome measure will be BPRS. Weekly
      blood will be drawn for drug levels of valnoctamide to be measured by gas chromatography
      (19). Each patient will receive valnoctamide or placebo for 5 weeks.

      Power Analysis:

      We have demonstrated significant effects as add-on in mania in this design with lithium (15),
      carbamazepine (16), and phenytoin (17). Each study had an N of about 40 patients, recruited
      over 18 months in each study. In each study as in the present proposal, a mood stabilizer or
      potential mood stabilizer was added to haloperidol at doses of physician's discretion for
      five weeks.

      Lithium adds clinically and statistically significant benefit to haloperidol treatment of
      mania (15) as does carbamazepine (16) and phenytoin (17). Such an "add-on" design is
      consistent with clinical practice and makes sense since dopamine blockers and mood
      stabilizers probably work by different mechanisms in mania. Valproate is typically used
      clinically in acute mania as an add-on to neuroleptics as well. Three positive studies
      published in excellent journals (15-17) from our group using this design are probably better
      than formal power analysis, which depends on a range of assumptions that are collapsible into
      the experience of our three studies. Because the prior probability of an effect of
      valnoctamide is lower than that of the above well-known compounds, we suggest recruitment of
      80 patients over 36 months to adequately power this study rather than the 40 patients in each
      of our previous studies. Since valnoctamide is no longer patented, orphan drug procedures or
      a use patent of the type granted to Abbott for divalproex sodium will be necessary to make
      this drug available for bipolar patients at risk for pregnancy in the future. An adequately
      powered study is therefore important at this stage.

      References

        1. Bialer M, Haj-Yehia A, Badir K, Hadad S: Can we develop improved derivatives of valproic
           acid? Pharm World Sci 1994; 16(1):2-6.

        2. Nau H, Headrick X: Valproic acid teratogenesis. ISI Atlas Sci Pharmacol 1987; 1:52-56

        3. Nau H, Hauck RS, Ehlers K: Valproic acid-induced neural tube defects in mouse and human:
           aspects of chirality, alternative drug development, pharmacokinetics and possible
           mechanisms. Pharmacol Toxicol 1991; 69(5):310-21.

        4. Bialer M: Pharmacokinetic considerations in the design of better and safer new
           antiepileptic drugs. J Control Release 1999; 62(1-2):187-92.

        5. Lemoine P, Fondarai J, Faivre T: Valpromide increases amplitude of heart rate circadian
           rhythm in remitted bipolar and unipolar disorders. A placebo-controlled study. Eur
           Psychiatry 2000; 15(7):424-32.

        6. Bialer M: Clinical pharmacology of valpromide. Clin Pharmacokinet 1991; 20(2):114-22.

        7. Bialer M, Haj-Yehia A, Barzaghi N, Pisani F, Perucca E: Pharmacokinetics of a valpromide
           isomer, valnoctamide, in healthy subjects. Eur J Clin Pharmacol 1990; 38(3):289-91.

        8. Haj-Yehia A, Bialer M: Pharmacokinetics of valpromide isomer valnoctamide in dogs. J
           Pharm Sci 1988; 77:831-834.

        9. Pisani F, Haj-Yehia A, Fazio A, Artesi C, Oteri G, Perucca E, Kroetz DL, Levy RH, Bialer
           M: Carbamazepine-valnoctamide interaction in epileptic patients: in vitro/in vivo
           correlation. Epilepsia 1993; 34(5):954-9.

       10. Loscher W, Nau H: Pharmacological evaluation of various metabolites and analogues of
           valproic acid. Anticonvulsant and toxic potencies in mice. Neuropharmacology 1985;
           24(5):427-35.

       11. Radatz M, Ehlers K, Yagen B, Bialer M, Nau H: Valnoctamide, valpromide and valnoctic
           acid are much less teratogenic in mice than valproic acid. Epilepsy Res 1998;
           30(1):41-8.

       12. US Patent 3,056,726 (1962): alpha-ethyl-beta-methylvaleramide for mental
           hyperirritability. McNeil Laboratories Inc.

       13. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS: Histone deacetylase is a
           direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen.
           J Biol Chem 2001; 276(39):36734-41.

       14. Shaltiel G, Shamir A, Belmaker RH, Greenberg ML, Agam G: Valproate inhibits inositol-P
           synthase: mood stabilization by inositol depletion elaborated. submitted

       15. Biederman J, Lerner Y, Belmaker RH: Combination of lithium carbonate and haloperidol in
           schizo-affective disorder: a controlled study. Arch Gen Psychiatry 1979; 36(3):327-33.

       16. Klein E, Bental E, Lerer B, Belmaker RH: Carbamazepine and haloperidol v placebo and
           haloperidol in excited psychoses. A controlled study. Arch Gen Psychiatry 1984;
           41(2):165-70.

       17. Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH: Phenytoin as an antimanic
           anticonvulsant: a controlled study. Am J Psychiatry 2000; 157(3):463-5.

       18. Yatham LN, Grossman F, Augustyns I, Vieta E, Ravindran A: Mood stabilisers plus
           risperidone or placebo in the treatment of acute mania. International, double-blind,
           randomised controlled trial. Br J Psychiatry 2003; 182:141-7.

       19. Bialer M, Hoch B: Rapid gas chromatographic assay for monitoring valnoctamide in plasma.
           J Chromatogr 1985; 337:408-411.
    

Intervention name(s): valnoctamide
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: valnoctamide; teratogenicity; double-blind; mania