Minocycline Augmentation to Clozapine

Schizophrenia is a major mental illness characterized by a variety of different symptoms
including hallucinations, paranoia, difficulties with formulating and expressing thoughts,
feelings similar to depression, and problems with cognitive processes. Individuals with
schizophrenia are usually treated with a class of medications called anti-psychotics, which
typically help alleviate some of the symptoms of the disorder. In general, anti-psychotic
medications do not completely cure the disorder, and many patients are left with some degree
of ongoing symptoms. Furthermore, it is estimated that 20-30% of individuals with
schizophrenia are considered treatment refractory or resistant and do not respond to
anti-psychotic medications. The Food and Drug Administration has approved one antipsychotic
medication for use in patients who are considered to have treatment resistant schizophrenia
(TRS). This medication, clozapine, has been shown to be beneficial for patients with TRS,
though as many as 40-70% of patients fail to respond or are partially responsive to treatment
with clozapine. In an extensive search of the medical and psychiatric literature, the study
team has been impressed by the potential of minocycline, a tetracycline antibiotic, as an
adjunctive therapy in patients with schizophrenia based on its reported neuroprotective and
anti-inflammatory effects. It is a fairly inexpensive drug, well tolerated, and two
randomized clinical trials have demonstrated favorable results in early-phase schizophrenia.
Only one case series with two patients has investigated minocycline in patients with
schizophrenia on clozapine. Minocycline is also an interesting medication for augmentation
with clozapine, as investigators are interested in previous findings of increased
inflammation in the brains of patients with schizophrenia and the potential role of
inflammation in treatment resistant schizophrenia. Though there are many markers of increased
inflammation in the brain, for this current study, investigators are interested in a general
marker of inflammation called C-Reactive Protein (CRP). The study team hypothesizes that some
patients may have increased levels of inflammation in the brain, as measured by the CRP level
(drawn from peripheral blood), and that those patients with increased levels of CRP may
respond better to augmentation with minocycline. The proposed pilot study will compare
minocycline augmentation with clozapine in individuals with high vs low inflammation as
measured by CRP. Investigators hypothesize that minocycline will be well tolerated and will
result in an improvement in the symptoms of schizophrenia, cognition, as well as improve the
quality of life for patients preferentially in patients with high CRPs. Investigators plan to
use a variety of different scales to measure improvement in the varying symptoms of
schizophrenia as well as cognitive function, which will be administered to patients at three
week intervals for a total study time of twelve weeks. Investigators hypothesize that
minocycline could prove to be an effective, well tolerated, and inexpensive medication for
treatment resistant patients with schizophrenia whom have particular difficulties with social
interactions, obtaining and maintaining employment, and overall quality of life. Furthermore,
investigators hypothesize that the data obtained in this study will contribute to the ongoing
exploration of the role of inflammation in the brain of patients with schizophrenia and help
understand and target the role of various inflammatory markers in the pathophysiology and
treatment of treatment resistant schizophrenia.

Inclusion Criteria:

- Mini International Neuropsychiatric Interview 6.0 diagnosis of schizophrenia or
schizoaffective disorder

- Persistent symptoms of schizophrenia as measured by one of the following PANSS items:
Total score ≥60, negative subscale ≥ 15, positive subscale ≥ 15, general
psychopathology subscale ≥ 30

- Currently taking clozapine and the dose has been adjusted within 100 mg of study
enrollment

- Currently taking clozapine for 3 months and documented clozapine level ≥ 350 ng/ml
prior to study start

- No other psychotropic medication changes for one month prior to study enrollment

- No new psychosocial interventions for one month prior to study enrollment

- No prior experience on minocycline for greater than 1 week

- May be taking any other psychotropic, dermatologic, or gastrointestinal drugs

Exclusion Criteria:

- History of organic brain disease

- Diagnostic and Statistical Manual of Mental Disorders (DSM) IV-TR diagnosis of Mental
Retardation or Dementia

- DSM-IV-TR diagnosis of Alcohol or Substance Dependence within the last six months
(except nicotine)

- Pregnancy or lactation

- Known hypersensitivity to tetracyclines

- Current known infection

- Any known neurological disease or medical condition that could impact the measurement
of the constructs being assessed

- Inpatient psychiatric hospitalization for worsening of psychiatric symptoms, OR
worsening of symptoms requiring a new level of outpatient support, OR started on a new
anti-inflammatory medication for greater than one week duration, OR addition of a new
psychotropic medication for psychiatric symptom control

- A change in > 15% in PANSS score from the "Lead-In Visit" to the "M0 visit"