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Introduction:

Depression is a common and widespread mental disorder affecting millions of people worldwide; [6] Thus, this review is mainly aimed to focus upon the action mechanisms, side effects, toxicity and the logical analytical approaches possibly used in forensic toxicology for the identification of one or more Antidepressant Drugs and their metabolites from biological test matrices.

Antidepressant: Types & Functions

Antidepressant covers many varieties of drugs having different modes of actions like [16]

Figure: Mechanism action of Monoamine reuptake inhibitors (MAOIs), Tricyclic anti-deprassant (TCA) and Selective serotonin reuptake inhibitors (SSRIs).

According to the “Monoamine Theory of Depression,” (proposed by Schildkraut in 1965) the decrease in monoamine neurotransmission is thought to be responsible for inducing depression in an individual. Thus, medication with Antidepressantdrugs (TCAs, MAOIs, SSRIs, and SNRI etc.) rise in the amount of neurotransmitters. Tricyclic antidepressants (TCAs) and heterocyclic antidepressants (SSRIs, SNRIs) inhibit the norepinephrine transporter (NET) and the serotonin transporter (SERT) by competing for the binding site of the amine transporter results in the increase levels of both NE (Norepinephrine) and 5HT (5-hydroxytryptamine or Serotonine) in the synaptic cleft. In addition to this the Monoamine reuptake inhibitors (MAOIs) inhibits an enzyme MAO (monoamino oxidase) released from mitochondria (MO) which convert 5-HT to 5 hydroxyindole acetic acid (HIAA) and norepinephrine (NE) to 3-methoxy 4-hydroxy phenyl glycol (MHPG). This phenomenon increases the stores of NA and 5-HT thus contributes to higher level of Neurotransmitters in Brain. [19]

Adverse effects

Antidepressants are supposed to increase the risk of suicidal thinking and behavior, especially in children accompanying other depressive and psychiatric disorders. [17] [18] [19] The European Medicines Agency showed warning on the use of Antidepressants which might increase the risk of suicidal behavior in children and adolescents. [19] Thus, these drugs may be responsible for the fatality and intoxication and their growing rate all over the world may show threatening effects which is the matter of global concern. Thus, increasing prescription rate and adverse effects of antidepressant drugs results in a growing interest for their determination from biological matrices, proved to be very helpful in the field of Forensic.

Biological Samples use for the Screening of Antidepressant Drugs

Biological samples are the basic requirement of Forensic Toxicology as it solves several related questions which make basis of judgement, consultation and expertise for the field. The biological matrices generally encountered for analysis are urine [34], hair, nails, vitrous humour etc.

The most important and encountered biosample used for analytical purposes is Blood (plasma, serum). Toxicological effects can correlate more effectively with their concentrations in blood which can be determined qualitatively [42]

Another important biological sample is Urine which is a widely used specimen employed for screening, identification and testing of unknown drugs accompanying advantages that it forms in high amount, readily available, easy to collect and contains much useful information about the major metabolic functions of the body. [48]

A next alternative to the blood and urine specimen is the Oral fluid; for it's applications in therapeutic and toxicological drug monitoring [54]

When the analytical studies get concern with long duration of exposure to the detection window hair analysis makes a complementary approach for the detection of antidepressant drugs with the additional advantages that the hair sample can be stored at room temperature for a long time without degradation and it is easy to collect. [62]

Except from all the above described biomatrices very precise and rarely encountered biological sample is Vitreous Humor. It's a fluid mainly composed of water and hyaluronic acid (major component) found between the lens and retina of the eye proved to be the best choice for analytical examinations as it is relatively well isolated and protected from putrefaction. (Quoted reference) Two different fatality cases were reported where the extraction of drugs is done from Vitreous humor. One case has been reported of citalopram fatality where the extraction of drug is done from Vitreous humor yeilding concentration of citalopram (SSRI) less than 0.04mg/L and in second case venlafaxine fatality is reported where postmortem analysis revealed the concentrations of Fluoxetine (SSRI) and it's metabolite Norfluoxetine as 5.2 mg/l and 2.2mg/l respectively. [64]

Other than these specimens, body tissues like liver [71], cerebrospinal fluid etc. canalso encountered for toxic and therapeutic drug monitoring biological matrices.

Techniques for Sample Preparation

The bioanalytical methods form two basic approaches that are the sample preparation step and detection of the compound of interest. Several methods have been published for the determination of one or more antidepressants in biological matrices for therapeutic monitoring or for toxicological purposes. For making biological samples suitable for analytical purposes some treatments should be given to overcome the matrix effects such that the other materials should not interfere with the analytical separation that is the extractability of the analytes in the sample inturn the results of the analysis. [96] These techniques are rapidly gaining acceptance in bioanalytical seperations to reduce time and labor producing satisfactory results with high selectivity and sensitivity over a wide dynamic range, contributing as very fine detection techniques.

Commonly Prescribed New Generation Antidepressant Drugs and their Metabolites

Several new antidepressants that inhibit the serotonine (SERT) and norepinephrine transporters (NET) have been consistently using for therapeutic purposes. [108]

Sertraline is an effective and highly utilized SSRIs group of drug, [113]

Another SSRIs group of Antidepressant drug is Fluoxetine, using worldwide in the therapy of major depression. It is metabolized via N-demethylation by the [117] nitrogen phosphorous detector (NPD) (Thesis- 103) and electron capture detector (ECD) (Thesis- 76), used for the rapid analysis of fluoxetine from biological samples, achieved detection limits up to nanogram level.

Citalopram is a selective and potent serotonine reuptake inhibitor, [78]

Another very important group of Antidepressant drug is SNRIs includes drugs like Venlafaxine which inhibits serotonine, noradrenaline, and to a lesser extent dopamine reuptake. [117] (Thesis-82) is also used for determination of venlafaxine, provided satisfactory results.

In the majority of the published analytical methods for determination of Antidepressant drugs, gas chromatography and high-performance liquid chromatography is applied in combination to different kinds of columns (operating under different separation conditions), mobile phases and detectors. High-performance liquid chromatography is described for the determination of selective serotonine reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (SNRI) and their metabolites in human plasma using fluorescence, mass and photo-diod array detector; Micellar liquid chromatography, the technique which allowed direct injection of biological samples, utilized appropriately selected surfactants in the mobile phase to maintain solubilization of interfering proteins of biological samples.Other than chromatography, separation technique like capillary electrophoresis after in-line solid-phase extraction is described for the analysis sertraline, fluoxetine and fluvoxamine from plasma samples. A survey of most recent multiresidue analytical methods developed for the determination of different kinds of Antidepressant drugs in different types of biological test matrices with their specific cleanup procedures including the choice of mobile phase, stationary phase, detector system and validation data is summarized in the tabular form below.

TABLE

Analytical Method

Matrix

Analyte

Extraction method

Column

Mobile phase

Detector system

Limit of detection/quantification (ng/L)/ analytical range

References

LC-MS

Plasma

Fluoxetine and norfluoxetine

Automated SPE

XTerra MS C18

Formic acid in methanol and water

Triple stage, ESI, positive mode, SRM

Fluoxetine and norfluoxetine, m/z 310.3 and 296.2 resp.Linearity,0.5-50ng/mL for both the analyte.

81

LC-MS

Plasma

Fluoxetine and norfluoxetine

On-line extraction using column switching

Oasis HLB and Discovery HS C18

Formic acid in acetonitrile and water

ESI, positive mode, SIM

LOQ,25ng/ml for both .

141

LC- MS

Hair

citalopram and it's metabolites

liquid/liquid extraction

narrow bore C18

_

Tandem mass spectrometre

LOQ 25 pg/mg

61

HPLC

Plasma

Venlafaxine,desmethylvenlafaxine, N,O-didesmethylvenlafaxine

liquid-liquid extraction

Thermo BDS HYPERSIL C18

water (ammonium acetate: 30mmol/l, formic acid 2.6mmol/l, trifluoroacetic acid 0.13mmol/l) and acetonitrile (60:40, V/V)

MS/ESI

LOD were 0.4, 0.2, 0.3, and 0.2ng/ml for VEN, ODV, NDV and DDV resp.

134

HPLC

Plasma

Venlafaxine ,O-di desmethylvenlafaxine

solid-phase extraction with C1 cartridges

reversed-phase column -C8

75% aqueous phosphate buffer containing triethylamine and 25% acetonitrile

Fluorescence detector

LOQ 1.0ngmL−1 and LOD 0.3ngmL−1

39

GC-MS

oral fluid

amitryptiline, paroxetine and sertraline

solid-phase extraction with Bond elute column {Acid compounds were eluted with acetone while basic and neutral compounds with dichloromethane:isopropanol:ammonium (80:20:2, v/v/v)}

methylsilicone capillary column

Carrier gas He, Flow rate 0.8ml/min

selected-ion-monitoring (SIM) mode.

Between0.9 and 44.2ng/ml (LOQ)

55

HPLC

Plasma

citalopram and it's metabolites

SPE (Waters

Oasis HLB cartridges)

reversed-phase column -C18

40% acetonitrile: 60% aqueous tetramethylammonium perchlorate

Fluorescence detection at 300 nm, exciting at 238 nm

(LOQ) 1.5 ng mL−1 citalopram and desmethylcitalopram , 2.0 ng mL−1 for didesmethylcitalopram

124

HPLC

Plasma

fluvoxamine, paroxetine, sertraline, fluoxetine, citalopram, mirtazapine, milnacipram, venlafaxine, desmethylcitalopram, didesmethylcitalopram, norfluoxetine, O-desmethyl venlafaxine, desmethylmirtazapine

liquid-liquid extraction

Symmetry C8

acetonitrile-phosphate buffer 10 mM

UV (230 nm and 290 nm)

LOD, 25 to 500 ng/mL (100-2000 ng/mL for venlafaxine and its metabolite),
LOQ, 25 ng/mL (100 ng/mL for venlafaxine and its metabolite)

142

HPLC-MS

Blood

fluoxetine, paroxetine, sertraline, fluvoxamine, Citalopram, norfluoxetine, desmethylcitalopram, didesmethylcitalopram, desmethylvenlafaxine, and desmethylmirtazapine

liquid-liquid extraction.

XTerra RP18 column

Acetonitrile and ammonium formate buffer (4 mmol/L)

Tandem mass spectrometre

LOD, 5-500 ng/mL (20-2000 ng/mL for venlafaxine and desmethylvenlafaxine) and
LOQ, 5 ng/mL (venlafaxine and desmethylvenlafaxine: 20 ng/mL)

143

HPLC

Serum

fluvoxamine, milnacipran, paroxetine, sertraline, fluoxetine, citalopram, venlafaxine, desmethylcitalopram, didesmethylcitalopram and norfluoxetine

liquid-liquid extraction.

Beckman C18 reversed-phase column

(50%, v/v) acetonitrile in a sodium phosphate buffer (0.05 M with pH 3.8)

UV (200.4 nm)

15 ng/ml -fluoxetine, 25 ng/ml-venlafaxine, norfluoxetine, citalopram and its metabolites, 40 ng/ml- sertraline, 50 ng/ml-fluvoxamine

127

Capillary Liquid chromatography

Plasma

citalopram, fluoxetine, paroxetine and their metabolites

reversed-phase C8 SPE

Kromasil, C18

acetonitrile-45 mM ammonium formate (25:75, v/v).

UV

LOQ between 0.05 to 0.26 μM

42

HPLC

Plasma

fluoxetine and norfluoxetine

Sample treated with acetonitrile and isolated supernatants were directly injected

Discovery C18

0.1% formic acid in water and acetonitrile (40: 60)

ESI- Tandem Mass spectrometre, (m/z 310 → m/z 44.3 for fluoxetine, m/z 296 → m/z 134 for norfluoxetine)

LOD, fluoxetine, 0.02 ng/mL and 0.03 ng/mL, norfluoxetine

95

RP-HPLC

Serum

Sertraline

liquid- liquid extraction.

cyano column

63:37 (v/v) methanol-sodium phosphate buffer (0.05M) containing 2mLL−1 triethylamine

Fluorescence detector

LOQ up to 2ngmL−

111

LC-MS/MS

plasma

Sertraline, N-desmethyl sertraline

liquid-liquid extraction

Betasil C8 column

750 mL methanol + 250 mL deionized water + 2.5 mL, 1.0 M ammonium trifluoroacetate.

tandem mass spectrometry

SER, NDS were were m/z 306.2→159.0, 292.1→159.0, resp.

12

LC-MS/MS

Plasma

venlafaxine (VEN) and O-desmethyl venlafaxine (ODV)

SPE

Betasil C18 column

isocratic

tandem mass spectrometry

m/z 278.27→121.11 for VEN, m/z 264.28→107.10 for ODV

144

RP-HPLC

Pharmaceutical formulations.

Olanzapine, fluoxetine.

_

Inertsil C18 reversed phase column

40:30:30 (v/v/v) mixture of 9.5mM sodium dihydrogen phosphate, acetonitrile & methanol

UV

LOQ, 0.005 & 0.001μgmL−1 for olanzapine and fluoxetine resp.

145

HPLC-MS-MS

Plasma

Citalopram, fluvoxamine and paroxetine

On-line SPE with column switching.(Oasis/HLB)

Oasis HLB and Symmetry C18

Formic acid in water and acetonitrile

Triple stage, APCI, positive mode, SRM

LLOQ, 20 microg/ L for citalopram & fluvoxamine and 10 microg/L/ for paroxetine. LOD, 5 microg/ L for all

131

LC-MS(/MS)

Plasma

Citalopram

LLE

Hypersil BDS C8

Aqueous ammonium formate and acetonitrile

ESI, positive mode, SIM

Analytical range, Citalopram 0.50-250ng/mL

146

LC-MS(/MS)

Plasma

Fluoxetine and norfluoxetine

LLE

Lichrospher 100 RP-8 E

Aqueous ammonium formate and acetonitrile

ESI, positive mode, SIM

Analytical range, Fluoxetine 2.5-250ng/mL, norfluoxetine 10-250ng/mL

147

LC-MS(/MS)

Plasma

Sertraline

SPE

Beta Basic C-8

Aqueous ammonium formate and acetonitrile

Triple stage, ESI, positive mode, SRM

Analytical range, Sertraline 0.5-60.0ng/mL

148

LC-MS(/MS)

Plasma

Fluoxetine

Stir bar sorptive extraction

Luna C18

Aqueous ammonium acetate and methanol

ESI, positive mode, SIM

Analytical range, Fluoxetine 10-500ng/mL

74

LC-MS(/MS)

Plasma

Fluoxetine, citalopram, paroxetine and venlafaxine

SPE

C18

Aqueous ammonium acetate and acetonitrile

ESI, positive mode, SIM

Analytical range, Fluoxetine, citalopram, paroxetine, venlafaxine 5.0-1,000.0ng/mL

149

LC-MS

Plasma

Citalopram

liquid-liquid extraction

Hypersil BDS C8 microbore column

10mM ammonium formate- formic acid and acetonitrile (30:70 v/v)

Positive electrospray ionization with selected ion monitoring mode.

m/z- 325 citalopram, m/z- 281 imipramine, LOQ- 0.50 ng/ml.

75

HPLC-MS/ ESI

Plasma

Fluoxetine, citalopram, paroxetine and venlafaxine

SPE

Macherey- NA Gel C18 column

Water (formic acid 0.6%, ammonium acetate 30mmol/l) and acetonitrile, 35:65 (v/v)

Electron spray ionization

LOD, Fluoxetine 0.5, citalopram 0.3, paroxetine 0.3 and venlafaxine 0.1 ng/ml

80

HPLC

Plasma

Fluoxetine and Norfluoxetine

liquid-liquid extraction

Reverse phase C18 column

Phosphate buffer and acetonitrile

Fluorescence detector

LOD, 3mg/l

76

LC-MS(/MS)

Serum

20 antidepressants: amoxapine, amitriptyline, citalopram, clomipramine, dothiepin, doxepin, fluoxetine, imipramine, maprotiline, mianserin, paroxetine, sertraline, trimipramine, nortriptyline, monodesmethylcitalopram, desmethylclomipramine, desipramine, norfluoxetine, desmethylmianserin,N-des methylsertraline

On-line extraction using column switching

Cyclone and Xterra MS C18

Ammonium acetate in water, formic acid in acetonitrile and water

Triple stage, ESI, positive mode, SRM

Analytical range for all compounds, 10-500ng/mL

150

LC-MS/MS

Oral Fluid and Plasma

amitriptyline, imipramine, clomipramine, fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and venlafaxine and their metabolites nortriptyline, desipramine, norclomipramine and norfluoxetine.

Automated SPE

Sunfire C18 IS Column

Acetonitrile and ammonium formate buffer (pH 3.0; 2 mM)

tandem mass spectrometer (ESI+ mode) with triple quadrupole

LLOQ -2 ng/ L (except clomipramine LmsZLOQ -10 ng/ L) for both oral fluid and plasma

151

HPLC

Urine and Plasma

amitriptyline, imipramine and sertraline

hollow fiber-based (polypropylene) liquid phase microextraction

Zorbax Extend C18 column

0.02 M acetic acid solution and methanol (54:46) (pH 4.0)

UV-VIS

LOD found between 0.5 and 0.7 μg L−1

85

GC-MS

Urine

fluoxamine, fluoxetine, sertraline, venlafaxine, mitrazapine, citalopram

SPMES

CP-SIL C8

He- carrier gas (floe rate- 1.2 ml/min)

MS with Electron Impact Ionisation

Less than 0.4ng/ml-1

Salgado petinal

Abbreviations: APCI atmospheric pressure chemical ionisation, ESI eletrospray ionisation, LLE liquid-liquid extraction, LOD limitation of detection, LOQ limit of quantification, SIM single ion monitoring, SPE solid-phase extraction, SRM selected reaction monitoring , ESI electron spray ionization, UV ultraviolet, FD fluorescence detector, LC_TMS liquid chromatography tandom mass spectrometry, LC_MS, GC_MS gas chromatography mass spectrometry, RP-HPLC reverse phase high performance liquid chromatography.

Thus, this table is framed for the comparative study of the major analytical approaches used in the detection and identification of Antidepressant Drugs and their metabolites in different biological matrices in order to develop the new methods with the aim to increase the sample throughput and to improve the quality of analytical methods. Analytical methods for the detection of ADs and their metabolites in biological matrices are of interest in the field of forensic toxicology which involves the analysis of drugs and poisons in biological specimens and interpretation of the results to be applied in a court of law. Several analytical methods have been developed for analysis of these antidepressants in biological matrices. These methods provide a good precision and accuracy over the entire analytical range and allowing the development of very rapid and efficient analytical methods by using newer kind of analytical techniques.

Conclusion:

As the subject of Antidepressants toxicity is evolving, newer methods for their analysis are also evolving. However, some classes of Antidepressants drugs are less toxic and well tolerated but can lead to toxic or fatal drug interactions and these also encountered in many Clinical and Forensic cases. The research in this field is very active and results in a large number of papers published every year. Therefore, this review is mainly aimed to target latest analytical and instrumental methods used in the detection and characterization of various Antidepressant drugs and their metabolites in biological test matrices in turn focused on their toxic as well as therapeutic aspects which would be definitely prove to be helpful in future research and still there is lots of work required in this area as it's prescription rate and toxicity is evolving day by day all over the world. Non-destructive and sophisticated instrumental techniques can also build a new strategy of examination and investigation for the drugs of interest. Future trials should also consider, using different kinds of detecting techniques and methods which would allow for easier comparison and interpretation of results across studies as the subject is of global concern. Despite the success of all validate methods there is a continuing need for sustained innovations in bioanalytical studies releated to forensic cases which needs fast, sensitive and non-destructive methods of analysis. Thus, future work in this area will definitely prove to be a promising from forensic prospect.

Acknowledgement:

This study is carried out at the Department of Research and Development, Gujarat Forensic Sciences University, Gandhinagar, India.

I am indebted to Professor Y. K Agrawal, Director, Department of Research and Development, Gujarat Forensic Sciences University, for giving support, encouragement and moreover the valuable guidance during preparation of this article.

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Exams can be one of the most stressful experiences you’ll ever have! Revision is key, and we’re here to help. With custom created revision notes and exam answers, you’ll never feel underprepared again.