Determination of Antidepressants and Antipsychotics in Dried Blood Spots (DBSs) Collected from Post-Mortem Samples and Evaluation of the Stability over a Three-Month Period
Abstract
:1. Introduction
2. Results
3. Discussion
3.1. Pre-Analytical Issues
3.2. Analytical Issues
3.3. Stability Study
4. Materials and Methods
4.1. Reagents and Chemicals
4.2. Instrumentation and Chromatographic Conditions
4.3. Sample Collection and Storage
4.4. Sample Preparation
4.5. Stability Studies
4.6. Validation Procedure
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of the compounds are not available from the authors. |
Substance Antidepressants | LOD (ng/mL) | LOQ (ng/mL) | Substance Antipsychotics | LOD (ng/mL) | LOQ (ng/mL) |
---|---|---|---|---|---|
Amitriptyline | 0.6 | / | Amisulpride | 0.2 | 5.0 |
Citalopram | 2.3 | 5.0 | Asenapine | 4.1 | / |
Desipramine | 0.9 | / | Chlorpromazine | 0.4 | / |
N-Desmethyl-mirtazapine | 1.4 | 5.0 | Clotiapine | 1.8 | 10.0 |
Desvenlafaxine | 3.2 | 5.0 | Clozapine | 1.4 | / |
Dibenzepin | 0.3 | 5.0 | Dixyrazine | 1.3 | 5.0 |
Dothiepin | 1.8 | / | Duloxetine | 1.3 | / |
Fluoxetine | 1.6 | 5.0 | Fluphenazine | 0.3 | / |
Fluvoxamine | 1.9 | 5.0 | Haloperidol | 0.8 | 10.0 |
Maprotiline | 0.6 | / | Hydroxyzine | 0.9 | / |
Mianserin | 1.0 | / | Levomepromazine | 5.2 | / |
Mirtazapine | 2.2 | 10.0 | Olanzapine | 2.7 | / |
Nortriptyline | 0.5 | / | Paliperidone | 1.4 | 10.0 |
Paroxetine | 0.6 | / | Pimozide | 2.1 | 5.0 |
Protriptyline | 2.0 | / | Promazine | 0.1 | / |
Reboxetine | 1.1 | / | Promethazine | 2.0 | / |
Sertraline | 0.5 | / | Quetiapine | 0.8 | 10.0 |
Trazodone | 0.5 | 5.0 | Tiapride | 0.4 | / |
Trimipramine | 0.1 | 5.0 | Ziprasidone | 1.8 | / |
Venlafaxine | 0.1 | 5.0 |
Substance | Accuracy (bias%) | Intra-Day Precision (CV%) | Inter-Day Precision (CV%) | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
5 ng/mL | 10 ng/mL | 20 ng/mL | 100 ng/mL | 250 ng/mL | 5 ng/mL | 10 ng/mL | 20 ng/mL | 100 ng/mL | 250 ng/mL | 5 ng/mL | 10 ng/mL | 20 ng/mL | 100 ng/mL | 250 ng/mL | |
Amisulpride | 6.6 | 2.2 | 0.2 | 0.9 | 1.3 | 20.0 | 5.3 | 8.6 | 6.6 | 8.2 | 15.4 | 20.0 | 8.0 | 16.9 | 2.1 |
Clotiapine | / | 7.0 | 11.5 | 3.6 | 0.4 | / | 3.7 | 7.1 | 16.3 | 6.9 | / | 17.1 | 17.4 | 12.5 | 4.5 |
Haloperidol | / | 7.7 | 4.7 | 2.1 | 0.2 | / | 11.3 | 7.9 | 14.6 | 12.3 | / | 18.9 | 2.2 | 17.2 | 14.1 |
Paliperidone | / | 6.8 | 6.1 | 3.0 | 0.4 | / | 19.5 | 8.5 | 15.0 | 19.3 | / | 17.9 | 7.3 | 5.7 | 5.7 |
Quetiapine | / | 8.1 | 1.0 | 1.0 | 0.2 | / | 19.5 | 17.2 | 6.2 | 5.3 | / | 2.8 | 15.9 | 5.2 | 17.9 |
Citalopram | 4.5 | 1.6 | 4.0 | 1.8 | 0.3 | 9.3 | 18.2 | 4.9 | 9.7 | 4.2 | 4.5 | 18.6 | 13.2 | 7.6 | 8.1 |
Desvenlafaxine | 5.9 | 0.3 | 2.7 | 0.9 | 0.1 | 17.5 | 18.4 | 14.2 | 8.9 | 15.6 | 9.8 | 18.8 | 12.7 | 12.8 | 5.6 |
Dibenzepin | 5.6 | 3.8 | 1.3 | 0.4 | 1.6 | 19.8 | 20.0 | 11.0 | 18.1 | 2.2 | 7.2 | 6.3 | 8.4 | 14.8 | 1.2 |
Fluoxetine | 16.6 | 0.4 | 0.8 | 1.5 | 0.3 | 18.6 | 6.2 | 17.6 | 6.5 | 7.1 | 19.6 | 17.4 | 14.7 | 16.1 | 3.1 |
Fluvoxamine | 0.6 | 8.5 | 3.5 | 2.8 | 0.3 | 20.0 | 2.5 | 16.0 | 11.9 | 18.9 | 18.6 | 17.6 | 16.9 | 20.0 | 20,0 |
Mirtazapine | / | 10.5 | 1.6 | 3.0 | 0.5 | / | 15.9 | 11.9 | 18.6 | 7.0 | / | 20.0 | 10.0 | 10.2 | 5.9 |
N-Desmethyl-mirtazapine | 0.5 | 6.3 | 2.1 | 0.3 | 2.3 | 19.6 | 18.0 | 4.1 | 2.7 | 18.2 | 6.2 | 16.5 | 8.4 | 18.6 | 3.6 |
Trazodone | 12.9 | 2.0 | 0.6 | 1.7 | 0.1 | 18.9 | 19.9 | 15.6 | 15.3 | 5.5 | 4.9 | 20.0 | 5.7 | 9.6 | 7.8 |
Venlafaxine | 6.0 | 3.4 | 5.3 | 1.2 | 0.2 | 17.9 | 3.5 | 11.5 | 12.2 | 6.9 | 10.8 | 2.6 | 8.3 | 15.3 | 2.2 |
Substance | Recovery % | Matrix Effects % | ||||||
---|---|---|---|---|---|---|---|---|
5 ng/mL | 10 ng/mL | 20 ng/mL | 250 ng/mL | 5 ng/mL | 10 ng/mL | 20 ng/mL | 250 ng/mL | |
Amisulpride | 115.7 | 110.9 | 79,6 | 103.9 | +16.2 | +11.8 | +19.3 | +4.1 |
Clotiapine | / | 119.2 | 118.8 | 113.5 | / | +20.3 | −17.8 | −7.7 |
Haloperidol | / | 114.1 | 70.5 | 103.1 | / | −12.2 | −19.1 | +14.5 |
Paliperidone | / | 53.4 | 59.4 | 44.7 | / | +17.6 | −6.0 | +3.9 |
Quetiapine | / | 50.4 | 40.8 | 26.9 | / | +5.5 | +16.2 | +17.8 |
Citalopram | 99.2 | 98.5 | 66.9 | 92.1 | +1.5 | −12.9 | −12.8 | −1.9 |
Desvenlafaxine | 95.2 | 85.4 | 85.4 | 89.3 | −2.1 | −11.5 | +13.9 | −11.6 |
Dibenzepin | 117.8 | 106.4 | 76.5 | 103.9 | −10.4 | +19.7 | −4.3 | +20.5 |
Fluoxetine | 120.0 | 49.7 | 32.1 | 57.0 | −16.3 | −0.7 | +19.4 | +18.5 |
Fluvoxamine | 118.8 | 69.2 | 90.1 | 86.6 | −1.0 | −16.8 | −4.1 | +20.6 |
Mirtazapine | / | 116.7 | 77.0 | 101.6 | / | −0.6 | −18.5 | +4.6 |
N-desmethyl-mirtazapine | 102.4 | 117.6 | 87.1 | 87.3 | −18.6 | −18.5 | −16.5 | −3.6 |
Trazodone | 88.0 | 112.4 | 59.8 | 95.9 | −2.2 | −19.4 | −19.6 | +20.6 |
Venlafaxine | 116.4 | 118.7 | 87.3 | 94.4 | +0.6 | −10.2 | −13.7 | −13.2 |
Case Number | Substance | Blood Therapeutic Range Used in the Laboratory (ng/mL) | Concentration in DBS (ng/mL) |
---|---|---|---|
1 | Trazodone Paroxetine | 700.0–1000.0 10.0–50.0 | 91.1 671.6 |
2 | Fluvoxamine | 60.0–230.0 | 2366.0 |
3 | Mirtazapine N-desmethylmirtazapine | 30.0–80.0 / | 133.7 112.1 |
4 | Fluoxetine | 120.0–500.0 | 5.6 |
5 | Citalopram | 50.0–110.0 | 408.3 |
6 | Citalopram | 50.0–110.0 | 56.9 |
7 | Venlafaxine Desvenlafaxine | 100.0–400.0 100.0–400.0 | 362.5 523.5 |
8 | Dibenzepin Quetiapine Dixyrazine | 25.0–150.0 100.0–500.0 ≈300.0 | 483.4 2309.7 126.4 |
9 | Pimozide | 4.0–10.0 | 13.1 |
10 | Trazodone | 700.0–1000.0 | 162.0 |
11 | Quetiapine | 100.0–500.0 | 84.1 |
12 | Venlafaxine Desvenlafaxine | 100.0–400.0 100.0–400.0 | 25.6 479.5 |
13 | Paliperidone | 20.0–60.0 | 17.6 |
14 | Amisulpride | 100.0–400.0 | 527.2 |
15 | Venlafaxine Desvenlafaxine Quetiapine | 100.0–400.0 100.0–400.0 100.0–500.0 | 321.7 686.1 153.5 |
16 | Clotiapine Haloperidol | 5.0–170.0 5.0–40.0 | 24.5 19.0 |
Analytes (Number of Positive Cases) | Stability of the Analytes on DBSs Observed in the Present Study | Stability of the Analytes in Similar Matrices According to Previously Published Articles |
---|---|---|
Citalopram (n = 2) | Stable for the first 2 weeks in one case and for 3 weeks in the other one. Degradation >50% after 3-month storage. | |
Mirtazapine (n = 1) | Stable within the 3-month period. | |
N-desmethyl mirtazapine (n = 1) | Stable for the first 3 weeks, with a slight degradation (−24%) at T4. | |
Venlafaxine (n = 3) | Stable within the 3-month period. | |
Desvenlafaxine (n = 3) | Stable within the 3-month period (except for an apparent degradation at T1 in one case, not confirmed at further analyses). | |
Trazodone (n = 1) | Stable within the 3-month period. | / |
Dibenzepin (n = 1) | Stable for the first 3 weeks. Degradation >50% after 3-month storage on DBSs (but not in blood stored at −20° C). | / |
Fluvoxamine (n = 1) | Moderate degradation in the first week (about −30%), remaining substantially stable afterward. | / |
Fluoxetine § (n = 1) | Slight degradation after the first week of storage (about −20%), remaining stable at the further analyses. |
|
Paroxetine * (n = 1) | Stable within the 3-month period. |
|
Dixyrazine * (n = 1) | Stable within the 3-month period. | / |
Quetiapine (n = 3) | In one case, moderate increase in the first 3 weeks (<31%). In the other two cases, stable within the 3-month period (except for an apparent degradation of 29% at T1 in one of them, not confirmed at further analyses). |
|
Amisulpride (n = 1) | Stable within the 3-month period. | |
Haloperidol (n = 1) | Stable within the 3-month period. | / |
Pimozide * (n = 1) | Stable for the first 3 weeks. Degradation >50% after 3-month storage. | / |
Paliperidone (n = 1) | Stable for the first 3 weeks. Degradation >50% after 3-month storage on DBSs (but not in blood stored at −20° C). |
|
Clotiapine (n = 1) | Unstable after 2 weeks, with >70% loss after 3 months. | / |
Liquid Chromatography | |
Flow rate | 200 µL/min → 400 µL/min constant flow of 0.2 mL/min; gradient elution: 90% A maintained for 2.5 min, then from 90% to 10% A within 3.0 min, maintaining 10% A up to 10.0 min, and re-equilibration up to 20 min. |
Mobile phase | H2O 0.1% (v/v) formic acid (A) Acetonitrile 0.1% (v/v) formic acid (B) |
Type of elution | gradient |
Column | Kinetex C18 (100 × 2,1 mm, 5 µm particle size) (Phenomenex, Castelmaggiore, BO, Italy) Kept at 45° during the analysis |
Mass Spectrometry | |
Operative mode | Multiple reaction monitoring (MRM)—positive polarity using nitrogen as collision gas (pressure set at level 5). Dwell time: 30 ms. |
Ion spray voltage | 5000 V |
Source temperature | 350 °C |
Curtain gas | 15 PSI |
Nebulization gas (air) | 20 PSI |
Heating gas (air) | 25 PSI |
ANALYTE | Q1 (m/z) | Q3 (m/z) | DP *(V) | EP *(V) | CE *(V) | CXP *(V) |
---|---|---|---|---|---|---|
Antidepressants | ||||||
Amitriptyline | 278.1 | 233.3 | 102 | 10 | 25 | 5 |
278.1 | 91.2 | 102 | 10 | 35 | 3 | |
Citalopram | 325.1 | 109.2 | 100 | 9 | 35 | 4 |
325.1 | 262.3 | 100 | 9 | 28 | 6 | |
Citalopram-D6 | 331.1 | 109.1 | 85 | 10 | 37 | 5 |
331.1 | 262.1 | 85 | 10 | 28 | 10 | |
Desipramine | 266.9 | 72.2 | 71 | 10 | 28 | 11 |
266.9 | 208.3 | 71 | 10 | 33 | 10 | |
N-Desmethylmirtazapine | 252.0 | 195.2 | 95 | 9 | 32 | 8 |
252.0 | 209.1 | 95 | 9 | 32 | 9 | |
Desvenlafaxine | 265.0 | 58.1 | 62 | 10 | 48 | 7 |
265.0 | 202.0 | 62 | 10 | 25 | 8 | |
Dibenzepin | 295.9 | 250.9 | 90 | 10 | 35 | 10 |
295.9 | 209.2 | 90 | 10 | 47 | 10 | |
Dothiepin | 295.9 | 223.2 | 75 | 8 | 33 | 11 |
295.9 | 218.3 | 75 | 8 | 33 | 11 | |
Fluoxetine | 310.1 | 310.1 | 63 | 8 | 7 | 10 |
310.1 | 148.3 | 63 | 8 | 13 | 7 | |
Fluvoxamine | 319.0 | 258.3 | 69 | 8 | 16 | 7 |
319.0 | 71.2 | 69 | 8 | 29 | 11 | |
Maprotiline | 278.2 | 250.3 | 148 | 8 | 28 | 13 |
278.2 | 219.3 | 148 | 8 | 36 | 11 | |
Mianserin | 264.9 | 208.3 | 103 | 12 | 30 | 10 |
264.9 | 58.3 | 103 | 12 | 47 | 8 | |
Mirtazapine | 267.0 | 196.0 | 100 | 10 | 35 | 8 |
267.0 | 72.0 | 100 | 10 | 32 | 9 | |
Nortriptyline | 263.9 | 233.3 | 80 | 9 | 22 | 12 |
263.9 | 91.2 | 80 | 9 | 35 | 3 | |
Paroxetine | 330.4 | 192.3 | 144 | 9 | 30 | 9 |
330.4 | 70.2 | 144 | 9 | 49 | 11 | |
Protriptyline | 264.9 | 192.2 | 110 | 10 | 34 | 7 |
264.9 | 156.2 | 110 | 10 | 29 | 7 | |
Reboxetine | 313.8 | 176.0 | 81 | 10 | 31 | 29 |
313.8 | 91.1 | 81 | 10 | 43 | 3 | |
Sertraline | 306.0 | 159.2 | 63 | 8 | 37 | 7 |
306.0 | 275.2 | 63 | 8 | 18 | 6 | |
Trazodone | 372.2 | 176.3 | 97 | 9 | 35 | 8 |
372.2 | 148.2 | 97 | 9 | 48 | 6 | |
Trimipramine | 295.0 | 100.3 | 69 | 10 | 23 | 4 |
295.0 | 58.1 | 69 | 10 | 59 | 8 | |
Venlafaxine | 278.0 | 58.2 | 71 | 10 | 40 | 6 |
278.0 | 121.1 | 71 | 10 | 40 | 3 | |
Antipsychotics | ||||||
Amisulpride | 369.9 | 242.2 | 101 | 9 | 39 | 12 |
369.9 | 112.5 | 101 | 9 | 39 | 4 | |
Asenapine | 286.2 | 165.9 | 96 | 10 | 46 | 6 |
286.2 | 215.0 | 96 | 10 | 40 | 8 | |
Chlorpromazine | 318.8 | 86.2 | 78 | 7 | 29 | 3 |
318.8 | 246.2 | 78 | 7 | 34 | 12 | |
Clotiapine | 343.9 | 287.2 | 101 | 14 | 30 | 7 |
343.9 | 255.3 | 101 | 14 | 44 | 5 | |
Clozapine | 327.0 | 270.1 | 100 | 9 | 34 | 6 |
327.0 | 296.3 | 100 | 9 | 36 | 7 | |
Clozapine-D4 | 331.3 | 272.3 | 94 | 10 | 35 | 9 |
331.3 | 299.1 | 94 | 10 | 35 | 11 | |
Dixyrazine | 427.9 | 229.3 | 104 | 10 | 37 | 11 |
427.9 | 187.3 | 104 | 10 | 39 | 9 | |
Duloxetine | 298.2 | 154.1 | 38 | 8 | 8 | 5 |
298.2 | 188.0 | 38 | 8 | 8 | 7 | |
Fluphenazine | 437.9 | 171.3 | 109 | 10 | 38 | 8 |
437.9 | 143.3 | 109 | 10 | 45 | 6 | |
Haloperidol | 375.9 | 165.2 | 83 | 10 | 34 | 7 |
375.9 | 123.1 | 83 | 10 | 57 | 5 | |
Hydroxyzine | 376.1 | 202.2 | 64 | 10 | 26 | 10 |
376.1 | 166.2 | 64 | 10 | 70 | 7 | |
Levomepromazine | 330.0 | 100.3 | 72 | 14 | 30 | 4 |
330.0 | 243.2 | 72 | 14 | 33 | 12 | |
Olanzapine | 330.0 | 100.3 | 72 | 14 | 30 | 4 |
330.0 | 243.2 | 72 | 14 | 33 | 12 | |
Paliperidone | 427.3 | 207.2 | 122 | 10 | 40 | 8 |
427.3 | 110.1 | 122 | 10 | 60 | 2 | |
Pimozide | 462.1 | 328.4 | 126 | 10 | 43 | 8 |
462.1 | 109.2 | 126 | 10 | 88 | 4 | |
Promazine | 284.8 | 86.2 | 65 | 12 | 29 | 13 |
284.8 | 212.3 | 65 | 12 | 35 | 10 | |
Promethazine | 285.0 | 198.0 | 80 | 10 | 18 | 15 |
285.0 | 240.0 | 80 | 10 | 20 | 15 | |
Quetiapine | 384.5 | 253.5 | 96 | 10 | 31 | 6 |
384.5 | 279.1 | 96 | 10 | 34 | 7 | |
Quetiapine-D8 | 392.3 | 258.3 | 90 | 10 | 35 | 12 |
392.3 | 286.5 | 90 | 10 | 34 | 15 | |
Tiapride | 328.9 | 256.0 | 118 | 6 | 26 | 20 |
328.9 | 213.2 | 118 | 6 | 48 | 10 | |
Ziprasidone | 413.3 | 194.2 | 121 | 10 | 39 | 9 |
413.3 | 177.3 | 121 | 10 | 39 | 8 |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Moretti, M.; Freni, F.; Valentini, B.; Vignali, C.; Groppi, A.; Visonà, S.D.; Osculati, A.M.M.; Morini, L. Determination of Antidepressants and Antipsychotics in Dried Blood Spots (DBSs) Collected from Post-Mortem Samples and Evaluation of the Stability over a Three-Month Period. Molecules 2019, 24, 3636. https://doi.org/10.3390/molecules24203636
Moretti M, Freni F, Valentini B, Vignali C, Groppi A, Visonà SD, Osculati AMM, Morini L. Determination of Antidepressants and Antipsychotics in Dried Blood Spots (DBSs) Collected from Post-Mortem Samples and Evaluation of the Stability over a Three-Month Period. Molecules. 2019; 24(20):3636. https://doi.org/10.3390/molecules24203636
Chicago/Turabian StyleMoretti, Matteo, Francesca Freni, Beatrice Valentini, Claudia Vignali, Angelo Groppi, Silvia Damiana Visonà, Antonio Marco Maria Osculati, and Luca Morini. 2019. "Determination of Antidepressants and Antipsychotics in Dried Blood Spots (DBSs) Collected from Post-Mortem Samples and Evaluation of the Stability over a Three-Month Period" Molecules 24, no. 20: 3636. https://doi.org/10.3390/molecules24203636