Niacin Flushing as Marker of Cannabis Effects on Arachidonic Acid Pathways in Schizophrenia
Condition: Schizophrenia; Cannabis Abuse
MeSH terms: Marijuana Abuse; Schizophrenia
Study type: Observational

Summary: 
      Increasing evidence suggests modulating effects of cannabinoids on time of onset, severity,
      and outcome of schizophrenia. Efforts to discover the underlying pathomechanism have led to
      the assumption of gene x environment interactions including premorbid genetical vulnerability
      and worsening effects of continuing cannabis use. For a main characteristic of psychoactive
      delta-9-tetrahydrocannabinol is its affinity to biological membranes, which are known to be
      disturbed in schizophrenia patients and genetic high-risk populations.

      Here we assess an hypothesised association between premorbid lipid disturbance and metabolic
      effects of external cannabinoids in schizophrenia.

      Intensity of niacin (methylnicotinate) skin flushing, indicating disturbed
      prostaglandin-mediated processes, is used as peripheral marker of lipid-arachidonic acid
      pathways and investigated in cannabis consuming and non-consuming schizophrenia patients and
      in healthy controls. Methylnicotinate is applied in three concentrations onto the forearm
      skin. Flush response is assessed in three minute intervals over 15 min using optical
      reflection spectroscopy.
    

Detailed description: 
      Subjects Niacin skin tests are performed on acutely ill consecutively admitted schizophrenia
      patients suffering not more than two psychotic episodes. All meet DSM-IV criteria for
      paranoide schizophrenia. Diagnosis is made by two independent experienced psychiatrists and
      further supported by structured clinical interview (SCID IV) (Wittchen et al 1997). Majority
      of patients is treated mostly with atypical neuroleptic drugs. The patient population is
      subdivided in one group having used cannabis on a regular basis (≥ 0,5 g/d, at least 3 month)
      prior to admission, and another group having never used cannabis apart from unique trials.
      Cannabis consuming patients do not use any other drug or alcohol on a regular basis.
      Psychiatric symptoms are assessed using Brief Psychiatric Rating Scale (BPRS) (Overall and
      Gorham 1962), Scale of Assessment of Positive Symptoms (SAPS) (Andreasen 1984), Scale of
      Assessment of Negative Symptoms (SANS) (Andreasen 1983), and Symptom Check List 1990 Revised
      (SCL 90-R) (Kaplan et al 1998).

      Patients are compared to healthy volunteers recruited by newspaper advertisement including
      again one group of cannabis users (duration and dose of cannabis use as in patients) and one
      group without any cannabis experience. Controls are interviewed in-depth to rule out a
      current psychiatric diagnosis or psychiatric personal or family history. As in patients, SCL
      90-R is also applied in controls.

      All cannabis-using participants are tested positive for cannabinoids in urine at the time of
      niacin testing. Subjects with any current or history of skin disorders (eczema, atopical
      dermatitis, psoriasis) or recent treatment with steroids or non-steroidal antiinflammatory
      drugs (e.g. acetylsalicylic acid) are excluded from the study before niacin testing. The
      study is approved by the Ethics Committee of Friedrich-Schiller-University Jena. All
      participants give written informed consent to participate in the study.

      Niacin skin test protocol Methylnicotinate (C7H7NO2, 99%, Sigma-ALDRICH Chemie GmbH, Germany)
      is applied simultaneously in three dilutions (0.001 M, 0.01 M, 0.1 M) of 50 µl each to the
      skin at the inner side of the forearm using chambered plaster for epicutaneous testing. After
      90 sec the plaster is removed. Skin flushing is quantified before and up to 15 minutes after
      methylnicotinate exposure in 3-min intervals, starting 90 sec after removal of the
      methylnicotinate patches. Methylnicotinate solutions are freshly prepared for each test to
      prevent any influence of sunlight.

      Reflection spectroscopy Optical reflection spectroscopy (ORS) is applied as described in more
      detail by Smesny et al 2001. Skin content of oxygenated blood is assessed with a handheld
      optical reflection spectrometer (spectral range: 400 nm to 700 nm, area of measurement:
      diameter 5 mm), using the oxyhemoglobin (HbO2) absorption double peak at 542 nm and 577 nm.
      Each measurement is repeated three times (within 10 sec) and then averaged.

      Spectroscopic data are processed automatically creating difference spectra by subtraction of
      pre-stimulation reflection intensities (also measured three times) from test intensities. Two
      Gaussian curves are fitted to the HbO2-absorption double peak. The area under the resulting
      sum curve is taken as measure of current skin flushing (measured in arbitrary units [a.u.]).

      Data analysis We plan to conduct a repeated measure analysis of variance (ANOVA) with TIME
      (3, 6, 9, 12, 15 min) and methylnicotinate CONCENTRATION (0.001 M, 0.01 M, 0.1 M) as
      within-subject factors and GROUP (patients, controls) and CANNABIS (cannabis user, cannabis
      non-user) as between subjects factors. GENDER, and AGE are treated as co-variates. For
      post-hoc comparison of single values, Mann-Whitney-U-Tests are calculated. Psychopathological
      ratings of the SCL 90-R are compared between groups using an univariate ANOVA with the same
      between group factors (GROUP, CANNABIS) and co-variates (AGE, GENDER) as above. Furthermore,
      effects of cannabis use on SAPS, SANS, and BPRS are investigated within the patient group. In
      order to explore a possible association between age or psychopathological ratings and skin
      flushing, Spearman correlation coefficients will be calculated. Due to the high number of
      calculated coefficients the significance level will be set on p < 0.01.
    

Observational model: Defined Population
Time perspective: Other
Keywords: Schizophrenia,; Cannabinoids,; Arachidonic Acid,; Niacin,; Prostaglandins