In some cases (e.g., the gill, which is involved in both gas exchange and osmoregulation), the

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Examples currently on the market are isocarboxazid (Marplan), phenelzine (Nardil), and tranylcypromine (Parnate). Via inhibition of the enzyme MAO, these compounds may produce enhanced neural activity in circuits utilizing the neurotransmitters serotonin, norepinephrine, and dopamine. TCAs have been found to inhibit monoamine reuptake transporters, primarily for norepinephrine and serotonin. These latter compounds interact in various ways with monoamine neurotransmitter receptors or reuptake transporters. The prevailing hypothesis regarding antidepressant mechanism is that some sort of change in serotonin and/or norepinephrine synaptic chemistry underlies their clinical action, but exactly what sort of change remains obscure.

Molecular Weight

The selective serotonin reuptake inhibitors (SSRIs) are a class of pharmaceutical and personal care product (PPCP) that have received significant attention in terms of their potential as a “contaminant of emerging concern” (OW/ORD Emerging Contaminants Workgroup, 2008). Between 2005 and 2008, approximately 11% of Americans over the age of 12 reported taking antidepressants (Pratt et al., 2011). In 2010 254 million antidepressant prescriptions were written and by 2015 that number had reached 314 million, making antidepressants one of the most prescribed medications, second only to cholesterol-lowering compounds (Aitken et al., 2016). SSRIs enter the aquatic environment primarily through inadequate removal by wastewater treatment, but also via storm water runoff from agricultural fields holding treated livestock and via contamination of groundwater from landfills. The average concentration of individual SSRIs within the aquatic environment is approximately 0.01 μg·L− 1 with 50-fold higher concentrations being measured in streams dominated by wastewater effluent (Kolpin et al., 2002; Metcalfe et al., 2003; Metcalfe et al., 2010; Schultz et al., 2010). potential impacts of SSRI exposure cannot be directly

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extrapolated, since the tissue itself is not conserved.

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However, contamination of any given local environment is not just with one but with many SSRIs and, combined, their concentrations can amount to a considerable SSRI load. Indeed, concentrations of total SSRIs have been measured at approximately 3 μg·L− 1 in close proximity to wastewater effluents (Mennigen et al., 2011). Pharmaceutical compounds have specific targets, such as for sale priligy transporters, receptors or enzymes, and specific modes of action within humans. For example, the direct target of SSRIs is the serotonin transporter (SERT; SLC6A4), and, in humans, the inhibitory mode of action of SSRIs results in an increase in extracellular concentrations of the neurochemical serotonin (5-HT; 5-hydroxytryptamine), that ultimately leads to the relief of symptoms associated with major depression and anxiety. Because of their importance, pharmaceutical targets are typically evolutionarily and functionally conserved across the animal kingdom; that conservation is exploited during drug development and testing, in which most experiments are performed on mammalian models (i.e., rats, mice) and the potential effects extrapolated to humans.

Clinical phase unknown

In theory, the same cross-species extrapolation can be applied to fish and other aquatic organisms. Indeed, the Fish Plasma Model developed by Huggett et al. (2003) calculates a predicted fish steady state plasma concentration (FSSPC) achieved by exposure to waterborne concentrations of a given compound based on its hydrophobicity (i.e., log Kow). The model then goes on compare the measured human therapeutic plasma concentration (HTPC), which may exceed the affinity (Km or Ki) of its intended target, of a pharmaceutical to the FSSPC to calculate an effect ratio (HTPC: FssPC). A lower effect ratio (ER), which occurs when the FSSPC approaches HTPC, indicates a higher potential for the fish to respond to the pharmaceutical compound. Using an Adverse Outcome Pathway (AOP) framework (Ankley et al., 2010; Figs.

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1, 3, 5, 6), the intent of this review

Under development

Human SERT expressed in COS-1 cells. So while the Read-Across Hypothesis does not necessarily predict effect concentrations, it does give a logical way to predict the physiological and molecular targets in fish as circulating SSRI levels approach the HTPC. With respect to predicting the ecological impacts of SSRIs, the question then becomes whether the HTPC can be reached in fish exposed to environmentally realistic SSRI concentrations (Huggett et al., 2003). For individual SSRIs, this is currently not the case (Kolpin et al., 2002; Metcalfe et al., 2003; Metcalfe et al., 2010; Schultz et al., 2010). However, when considering total SSRIs (i.e., the sum of all SSRIs) within a contaminated environment, therapeutic levels may be within reach (Mennigen et al., 2011).

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In saying that, there are some differences between fish and mammals that may interfere with read-across. For one, the basic pharmacokinetic properties of each individual SSRI—absorption rate, half-life, metabolic conversion rate and toxicity buy priligy price of metabolites—are highly variable (reviewed by Hiemke and Härtter, 2000) and may differ between fish and mammals. For example, fish are poikilotherms and, even if held at the same temperature as mammals (37 °C), they inherently have lower metabolic rates, and thus may have slower uptake and clearance rates for pharmaceutical compounds than mammals of the same weight. Along these lines, the half-life of FLX and its primary metabolite, norfluoxetine (which is more potent than FLX itself), has been found to be longer in fish (9.4 days; Paterson and Metcalfe, 2008) compared to the half-life estimates reported for mammals (1–4 days; Hiemke and Härtter, 2000). Another difference is that fish do not have two of the major cytochrome P450 (CYP) isoenzymes believed to play a major role in the metabolic conversion of FLX to norfluoxetine (McRobb et al., 2014). is (1) to examine the similarities and differences in the

Not under development

Despite this, there is evidence that the conversion of FLX to norfluoxetine may be faster in fish compared to mammals (Margiotta-Casaluci et al., 2014; McRobb et al., 2014). Third, potential differences in pharmacokinetics may be overwhelmed by differences in dosing; unlike humans who receive a single daily dose of a pharmaceutical compound orally, fish are most likely to be continually exposed to the SSRI or a mixture of SSRIs in the water (Rand-Weaver et al., 2013). Next, while several studies have looked at the targets of pharmaceuticals and have found on average 60–70% sequence identity between fish and mammals (Gunnarsson et al., 2008; McRobb et al., 2014), slight nuances in molecular sequence can confer substantial changes in transport or binding affinity and, therefore, differences in sensitivity to a given compound. Thus, differences in molecular sequence identity could be inconsequential or could be significant, depending on the affected residues (Mortensen et al., 2001; Severinsen et al., 2008; McRobb et al., 2014). Finally, when considering read-across for SSRIs in particular, both molecular and functional conservation is required not only in their direct target, SERT, but in the 5-HT receptors that then respond to the resulting elevations in extracellular 5-HT, of which in mammals there are 14 different subtypes expressed in a variety of different tissues. molecular initiating event and the cellular response to SSRI treatment/exposure

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between mammals and teleost fish that will allow for predictions

Age Group	Average Dosage (mg)	Common Usage Duration	Frequency per Week
25-34	30	3-6 months	2-3 times
35-44	60	6-12 months	1-2 times
45-54	30	As needed	1-2 times
55+	60	Variable	Once

based on the Read-Across Hypothesis, (2) to review the known

As seen in

Essentially, this model illustrates a method to use information regarding human and small mammal efficacy of pharmaceutical compounds to guide predictions of impact in fish, describing a more informed approach to toxicological studies involving pharmaceutical compounds that has gained momentum over the past few years. This Read-Across Hypothesis (Huggett et al., 2003; Berninger and Brooks, 2010; Winter et al., 2010; Rand-Weaver et al., 2013), or the idea that similar plasma or tissue concentrations of a given pharmaceutical will cause comparable target-mediated effects in both humans and fish if the targets are functionally conserved, has recently been validated for teleost fish and SSRIs (Valenti et al., 2012; Margiotta-Casaluci et al., 2014). (2012) exposed fathead minnows (Pimephales promelas) to waterborne sertraline at concentrations of 2.8, 9.4 and 28.1 μg·L− 1for 28 days that resulted in plasma concentrations (305–1927 ng·mL− 1) above the HTPC (5–250 ng·mL− 1). At these plasma levels, consistent with human therapeutic effects, there were reductions in the amount of SERT [3H]-citalopram binding and in shelter-seeking behavior, which was interpreted as a lowered anxiety (anxiolytic). The same species of minnow were also exposed to waterborne FLX concentrations (20, 38 and 72 μg·L− 1 for 28 days) which resulted in plasma FLX concentrations that were similar to or greater than the HTPC (91–302 ng·mL− 1) (Margiotta-Casaluci et al., 2014).

Phase 1/2

As predicted, FLX at these doses induced anxiolytic effects similar to humans while no measurable effects were observed at a HTPC: FSSPC of < 1 (Margiotta-Casaluci et al., 2014). However, this is not always the case; there are many studies that report impacts of FLX and other SSRIs when fish are exposed to concentrations that are predicted to produce FSSPCs well below the HTPC (for e.g., Henry and Black, 2008; Dzieweczynski and Hebert, 2012; Barry, 2013; Pelli and Connaughton, 2015; Dzieweczynski et al., 2016, to name a few). However, the HTPCs for both FLX and sertraline are significantly higher than the reported Ki (affinity of the inhibitor) of these SSRIs for SERT (Table 1) which could explain why an effect may be measured below the HTPC. Reported fish and human SERT Ki values for SSRIs, tricyclic antidepressants and 5-HT. Zebrafish or human SERT expressed in human embryonic kidney (HEK) cells. role of 5-HT receptors within fish to predict how they

Parameter	Values	Notes
Absorption Time	1-2 hours	Peak plasma concentration
Half-life	19 hours	Duration of action
Metabolism	Liver (CYP2D6 enzyme)	Some variability based on genetics
Excretion	Urine	Primarily unchanged

may impact organ and organ-system level responses to SSRI exposure and (3) to uncover potentially understudied endpoints for SSRI toxicity.

Aspect	Positive Feedback (%)	Negative Feedback (%)	Common Concerns
Effectiveness	70%	5%	Mild nausea
Quick Onset	65%	3%	Headache
Duration of Effect	60%	4%	Dizziness
Side Effects	20%	20%	Fatigue, dizziness