1) Aim of this study
This paper is an independent Humanitarian work that brings the world a critically needed paradigm of scientific neurobiochemistry to safely and effectively help people who have a Bipolar Disorder.
2) Design of this study
This paper is based on data found online in approximately 120 existing documents (see Description of Materials Used in This Study below).
3) Setting of this study
This author owns and operates a one-person private practice Mental Health clinic that is not used for experimental research. This author’s research consists of extensively gathering and analyzing information documents and research studies found on the internet.
4) Characteristics of study participants
Four of this author’s Bipolar Disorder clinical patients and two of their household family members signed consent forms allowing medication-pertinent treatment information to be mentioned in this paper. These were not experiment subjects. They did not actively participate in this study.
5) Description of materials used in this study
Internet searches gathered a wide range of scientific research documents, prescription guidelines, drug product package inserts, letters and other documents exchanged back and forth between the FDA and the manufacturer, FDA documents evaluating the manufacturer’s Approval Application research reports, clinical efficacy research studies, laboratory in-vivo investigations of chemical properties and interactions.
6) Description of the processes used in this study
See #5 above
7) Interventions used in this study
No experimental interventions were used in this study.
8) Comparisons used in this study
Risperidone was compared to Paliperidone vis á vis review and analysis of data in existing documents found online regarding dose-related clinical efficacy, duration of clinical efficacy, chemical structure, duration of chemical structure, neurobiochemical properties, neurobiochemical actions and potentials, histories of product development, and histories of FDA approvals
9) Type of statistical analysis used in this study
Basic Algebra was used for calculating Risperidone dose-amounts, plasma concentrations, and activation thresholds.
Differential-activation: Activating Risperidone while neutralizing Paliperidone
The neuropsychiatric benefits of Risperidone can be activated without neural responses to Paliperidone. To the best knowledge of this author this is the first research paper regarding differential-activation of Risperidone and Paliperidone. This is the first research paper to show differential-activation is possible. This research paper also is the first to present a treatment method that activates the benefits of Risperidone without activating responses to Paliperidone. This topic is new and critically important for the treatment for Bipolar Disorders.
Many people in the Medical and Research Communities are aware that Serotonin destabilizes Bipolar Disorders and that Risperidone is a Serotonin antagonist. The vast majority of Medical and Research people are unaware that metabolite Paliperidone is a Serotonin agonist that needs to be neutralized for safe and effective treatment of Bipolar Disorders. Key factors for accomplishing this critically necessary differential-activation include:
A) At about 4-hours Risperidone metabolizes into other chemicals including Paliperidone.
B) Risperidone efficacy occurs at low serum concentrations  that metabolize inactive small amounts of Paliperidone .
C) Risperidone metabolizes into 77.35% of its volume in Paliperidone, yielding 22.65% less Paliperidone than Risperidone .
D) The activation-threshold serum concentration of Paliperidone is three times higher than activation-threshold of Risperidone .
To the best awareness of this author, this is the first paper to show that it is beneficial to activate the psychoactive properties of chemical-Risperidone while not activating the psychoactive properties of Paliperidone. To the best awareness of this author, this is the first paper to show that it is possible to activate to activate the psychoactive properties of chemical-Risperidone while not activating the psychoactive properties of Paliperidone. To the best awareness of this author, this is the first paper to show how to activate the psychoactive properties of chemical-Risperidone while not activating the psychoactive properties of Paliperidone. When providing clinical treatment for Bipolar Disorders it is critical to differentially activate the former and not the latter. Chemical-Risperidone is a powerful Serotonin and Dopamine antagonist. Paliperidone is a harmful Serotonin agonist and a weak Dopamine antagonist. Key factors for calculating a differential-activation regimen include:
1) Efficacy of Risperidone occurs at low serum concentrations.
2) At about 4-hours Risperidone metabolizes into other chemicals.
3) The metabolites are inert other than Paliperidone.
4) The serum concentration activation-threshold of Paliperidone is three times higher
than the serum concentration activation-threshold of Risperidone .
5) Risperidone metabolizes into 77.35% of its volume in Paliperidone, yielding 22.65%
less Paliperidone than Risperidone .
An active-moiety research article by Odou et al studied Paliperidone serum concentrations in relationship to clinical-efficacy. The authors wrote, “Statistical analysis revealed a significant increase in efficacy when the serum concentration of active drug was between 25 and 150 µg/L…” This author marked the level of clinical efficacy from Paliperidone 25 µg/L with vertical red line in Figure 5 below. Figure 6 below shows “active-moiety” (Paliperidone) plasma concentration levels and corresponding Risperidone dose-amounts per day.
On Graph F this author marked 25 µg/L with a horizontal green line that intersects the Curve-1 efficacy-mean at the 0.051 mg/kg point. This is equivalent to 4.627 mg for a 200-pound person, 3.933 mg for 170-pounds, 3.47 mg for 150-lbs, 3.0073 mg for 130-lbs, 2.6603 mg for 115-lbs, or 2.3133 mg for 100-lbs. This yields Paliperidone 25 µg/L and the above-mentioned significant increase in clinical efficacy .
The phrase “significant increase in efficacy” said minimal efficacy occurred at a lower concentration than 25 µg/L. This author re-analyzed the data and found minimal Paliperidone efficacy occurred at 23.9 µg/L (see Figure 7 below). This corresponds with Risperidone .05 mg/kg, equivalent to 4.5 mg for a 200-lb person, 3.75 mg for 170-lbs, 3.5 mg for 150-lbs, 3 mg for 130-lbs, 2.5 mg for 115-lbs, or 2.25 mg for a 100-lb person (see Figure 8 below) .
The above study listed mg/kg dosages per body weight. The average weight of USA males is 197.9 pounds  and 170.6 pounds for females  (see Figure 9 and Figure 10 below). According to data from the above study, minimum clinical efficacy of Paliperidone requires a Paliperidone serum concentration of 23.9 µg/L. That requires Risperidone daily dose-amounts of 4.48 mg for average-weight males and 3.87 mg for average-weight females  (see Figure 9a and Figure10a below).
The 4.48 mg and 3.87 mg dose-amounts were for average-weight USA Americans. Such persons are significantly overweight. Their dose-amounts may be too high for persons of healthier weight. In order to find dose-amounts for persons of healthier weight, this author used the weight-range means for average height males (5’9”, 156.66 pounds) and females (5’4”, 131.33 pounds). The calculated daily dose-amount for healthier-weight men is 3.55 mg and 2.98 mg for healthier-weight women (see Figure11, Figure11a, Figure 12, and Figure 12a below) [12, 13].
The calculated dose-amounts for healthier-weight and average-weight USA Americans correspond to the Paliperidone serum concentration that was associated with minimal clinical efficacy on CGI2 test-scores. The clinical efficacy dose-amounts and serum concentration seem to affirm a synaptic-activation threshold but biochemical data is needed in order to correctly identify a synaptic threshold and dosage parameters.
Factors for calculating dose-amounts that activate Risperidone without activating Paliperidone
Factors for calculating appropriate dose-amounts include but are not limited to:
- The appropriate Risperdal/Risperidone doses are 3.2265 times less than doses that activate Paliperidone. This is a biochemical ratio with two inherent properties:
- The needed amount of Risperidone serum concentration is three times less than the amount of Paliperidone serum concentration that affects synaptic functions6.
- Risperidone metabolizes into 22.65% less Palideridone than the original amount of Risperidone2.
- Risperidone has an onset time of 15-20 minutes, a half-life of 3.2-3.5 hours, and its clinical efficacy and chemical-structure end at 4 hours .
Steady efficacy requires a steady serum concentration that requires taking Risperidone every 3.8 hours. Due to the frequency, routine small doses plus small extra doses taken as needed provide steady efficacy without overmedicating the patient and without activating Paliperidone. When a patient is starting Risperidone (or any psychoactive medication), introduce it slowly in a way that minimizes and/or prevents grogginess. Keep in mind that medication-grogginess is a tiredness of the body, muddied/slow thinking, and flat or irritable emotions. Medication-grogginess is the leading cause of poor adherence and quitting treatment among Bipolar Disorder patients. The new treatment paradigm in this paper prevents medication-grogginess.
Calculating differential-activation dose-amounts
Differential-activation is defined herein as an induction of neural responses to Risperidone without an induction of neural responses to Paliperidone. Differential-activation requires maintaining Paliperidone at below the serum concentration that induces neural responses to Paliperidone. The preceding re-analyses of clinical data calculated the threshold concentration of Paliperidone and the threshold doses of Risperidone. In addition to clinical data, differential-activation incorporates laboratory findings and biochemical variables such as 1) Risperidone metabolizes into a 22.65% lesser amount of Palideridone, and 2) Neural responses to Paliperidone require a serum concentration that is three times higher (a 3/1 ratio) than the Risperidone response-threshold.
The calculated Risperidone serum concentration clinical efficacy threshold is 6.5 µg/L (see Table 1 below). This is 27.2% of the Paliperidone efficacy-threshold. Thus, differential-activation occurs when a Risperidone serum concentration is below 27.2% of the Paliperidone threshold. Dose amounts for differential-activation vary according to body weight and severity of symptoms, and the severity of Bipolar symptoms fluctuates over time. Body weight is a useful constant factor in calculating dose-amounts and it can useful for preliminary calculations of five-times-per-day low doses. Computations for dosages per body weights [14, 15, 16, 17] and serum concentrations are provided in Table 1 and Table 2.